Skills in Rheumatology 9789811583223, 9789811583230

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Skills in Rheumatology
 9789811583223, 9789811583230

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Table of contents :
Introduction
How to Use This Book?
Acknowledgement
Contents
About the Editors
Part I: Basics in Rheumatology
1: History-Taking Skills in Rheumatology
1.1 Introduction
1.1.1 Objectives
1.2 Approach to History Taking in Rheumatology
1.3 Historical Correlation
1.4 Physical Examination
1.5 How to Present your Case
1.5.1 Impression
1.5.2 Problem List
1.6 Follow-Up Patient
1.7 The 2011 ACR/EULAR Definitions of Remission in Rheumatoid Arthritis Clinical Trials
1.7.1 Boolean-Based Definition [2]
1.7.2 Index-Based Definition
References
2: Approach to Musculoskeletal Examination
2.1 Introduction
2.1.1 Objectives
2.2 Epidemiology of Rheumatic Diseases
2.3 Current Status of MSK Examination
2.4 General Approach to MSK Examination
2.5 Musculoskeletal Examination of Upper Limb Joints (Fig. 2.1)
2.5.1 The Hand and Wrist Joints
2.5.1.1 First Step: The Anatomy
Anatomy of the Hand Joints (Fig. 2.1)
Approach to Hand Pain
2.5.1.2 Second Step: The Approach
Inspection
Screening Exam
Palpation
Range of motion
Special tests
2.5.2 The Elbow Joint
2.5.2.1 First Step: The Anatomy (Figs. 2.7 and 2.8)
Approach to Elbow Pain
Differential Diagnosis
2.5.2.2 Second Step: The Approach
Inspection
Screening Exam
Palpation
Range of Motion
Special Tests
Golfer’s Elbow Test
Tennis Elbow Test
Elbow Flexion Test (Ulnar Nerve)
2.5.3 The Shoulder Joint
2.5.3.1 First Step: The Anatomy (Fig. 2.15)
Approach to Shoulder Pain
2.5.3.2 Second Step: The Approach
Inspection
Screening Exam
Palpation
Range of Motion
Special Tests
For RCT
Infraspinatus and Teres Minor
Left off Test
Hawkins Impingement Sign
Drop Arm Test (Fig. 2.22)
For AC joint:
2.6 Musculoskeletal Examination of the Lower Limb Joints
2.6.1 Ankle Joint
2.6.1.1 First Step: The Anatomy
Approach to Ankle Pain
2.6.1.2 Second Step: The Approach
Inspection
Screening Exam
Palpation
Range of Motion (Fig. 2.30)
Special Tests
2.6.2 Musculoskeletal Examination of the Knee Joint
2.6.2.1 First Step: The Anatomy (Fig. 2.35)
Approach to Knee Pain
2.6.2.2 Second Step: The Approach
Inspection
Screening Exam
Palpation
Range of Motion
Special Tests
2.6.3 Musculoskeletal Examination of the Hip Joint
2.6.3.1 First Step: The Anatomy (Fig. 2.39)
Approach to Hip Pain
2.6.3.2 Second Step: The Approach
Inspection
Screening Exam
Palpation
Range of Motion
Special Tests
2.7 Back Examination
2.7.1 First Step: The Anatomy
2.7.2 Second Step: The Approach
2.7.2.1 Inspection
2.7.2.2 Screening/Gait Assessment
2.7.2.3 Palpation
2.7.2.4 Range of Motion
2.7.2.5 Special Tests
Straight Leg Raising Test (SLRT) (Fig. 2.54)
Slump Test (Fig. 2.56)
Sacroilliac Joints Exam
Modified Schober’s Test
Neurological Exam
References
3: Laboratory Interpretation of Rheumatic Diseases
3.1 Introduction
3.1.1 Objectives
3.2 Acute Phase Reactants
3.3 Rheumatoid Factor (RF) and Anti-citrullinated Protein Antibody (ACPA)
3.3.1 Definition
3.4 Antinuclear Antibodies (ANAs)
3.4.1 Definition
3.4.2 Methods of Measurement
3.5 ANA Profile
3.5.1 Definition
3.6 Other Disease-Specific Antinuclear Antibodies and Cytoplasmic Antibodies
3.7 Circulatory Complement Components
3.7.1 Mechanism of Acquired Complement Deficiencies
3.8 Synovial Fluid Analysis
3.9 Key Notes
3.9.1 Gram Stain
3.9.2 Synovial Fluid Culture
3.9.3 Diagnostic Approach
3.9.4 Crystal Search Using Polarized Light Microscopy
3.10 Summary
References
4: Pharmacotherapy in Systemic Rheumatic Diseases
4.1 Introduction
4.2 Learning Objectives
4.3 Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
4.4 Synthetic Disease-Modifying Anti-Rheumatic Drugs (sDMARDs)
4.4.1 Methotrexate
4.4.2 Leflunomide
4.4.3 Azathioprine
4.4.4 Hydroxychloroquine
4.4.5 Sulfasalazine
4.4.6 Mycophenolate Mofetil
4.4.7 Cyclophosphamide
4.4.8 Tofacitinib
4.4.9 Apremilast
4.5 Biological Disease-Modifying Anti-Rheumatic Drugs (bDMARDs)
4.5.1 TNF-α Blockers
4.5.2 Rituximab
4.5.3 Abatacept
4.5.4 Tocilizumab
4.5.5 Ustekinumab
4.5.6 Secukinumab
4.6 Glucocorticoids
4.7 Anti-Resorptive Drugs
4.7.1 Bisphosphonates
4.7.2 Raloxifene
4.7.3 Teriparatide
4.7.4 Denosumab
4.8 Drugs Used in Crystal Arthropathy
4.8.1 Colchicine
4.8.2 Allopurinol
4.9 Symptom-Specific Drugs
References
5: Radiology in Rheumatology
5.1 Introduction
5.2 Learning Objectives
5.3 Infectious Arthritis
5.3.1 Septic Arthritis
5.3.1.1 Radiographs
5.3.1.2 Ultrasonography
5.3.1.3 CT Scan
5.3.1.4 MRI
5.3.1.5 Scintigraphy
5.3.2 Tuberculous Arthritis
5.3.2.1 Radiograph
5.3.2.2 Ultrasonography
5.3.2.3 CT Scan
5.3.2.4 MRI
5.3.3 Brucella Arthritis
5.3.3.1 Radiograph
5.3.3.2 Ultrasonography
5.3.3.3 CT Scan
5.3.3.4 MRI
5.3.3.5 Scintigraphy
5.4 Metabolic Arthritis
5.4.1 Gouty Arthritis
5.4.1.1 Radiographs
5.4.1.2 Ultrasonography
5.4.1.3 CT Scan
5.4.1.4 MRI
5.4.2 Calcium Pyrophosphate Dehydrate (CPPD) Deposition Disease or Pseudogout
5.4.2.1 Radiograph
5.4.2.2 Ultrasonography
5.4.2.3 CT Scan
5.4.2.4 MRI
5.4.2.5 Radiographs
5.4.2.6 Ultrasonography/Magnetic Resonance Imaging (MRI)
5.5 Summary
5.5.1 Active Inflammatory Findings
5.5.2 Chronic Inflammatory Findings
References
Part II: Diagnostic Approach to Common Medical Problems in Patients with Rheumatic Diseases
6: Low-Back Pain
6.1 Introduction
6.2 Learning Objectives
6.3 Definition
6.4 Prevalence
6.5 Differential Diagnosis
6.6 Approach to Diagnosis
6.7 Radiological Studies for LBP
6.8 Detection of Inflammatory Back Pain
6.9 Treatment of Low-Back Pain (Acute or Sub-Acute Pain) [17, 18]
6.10 Treatment of Inflammatory Back Pain (IBP)
6.11 Referral
References
7: Pulmonary Manifestations of Connective Tissue Diseases
7.1 Introduction
7.2 Chapter Objectives
7.3 About the Chapter
7.4 To Get the Most of the Chapter
7.5 Important Information about Pulmonary Manifestations of CTDs before Going through the Chapter
7.6 Pulmonary Manifestations According to each CTD
7.6.1 Systemic Sclerosis or Scleroderma (SSc)
7.6.1.1 Parenchymal Lung Diseases
Presentation
Diagnosis
Prognosis
Treatment
Aspiration Pneumonitis
7.6.1.2 Vascular Diseases
Introduction
Presentation
Screening
Diagnosis
Prognosis
Treatment
7.6.1.3 Airway Disease
Bronchiectasis
Pleural Involvement
Pleural Effusion
Spontaneous Pneumothorax
Respiratory Muscle Weakness
7.6.1.4 Systemic Lupus Erythematosus (SLE)
Background
Pulmonary Manifestations
Pleural Diseases
Pleural Effusion
Presentation
Diagnosis
Treatment
7.6.1.5 Parenchymal Lung Disease
Acute Lupus Pneumonitis (ALP)
Introduction
Presentation
Diagnosis
Treatment
Prognosis
7.6.1.6 Diffuse Alveolar Hemorrhage (DAH)
Introduction
Presentation
Diagnosis
Treatment
Prognosis
7.6.1.7 Chronic ILD
Introduction
Presentation
Diagnosis
Treatment
Prognosis
7.6.1.8 Pulmonary Vascular Diseases
Thromboembolic Disease
Introduction
Presentation
Diagnosis
Treatment
Prognosis
7.6.1.9 SLE-Associated Pulmonary Arterial Hypertension (SLE-PAH)
Background
Presentation
Screening
Treatment
Acute Reversible Hypoxia
7.6.1.10 Airway Disease
Upper Airway Involvement
Introduction
Presentation
Diagnosis
Treatment
Lower Airway Involvement
Bronchiectasis
Bronchiolitis Obliterans (BO)/Obliterative Bronchiolitis (OB)
7.6.1.11 Muscle Involvement
Shrinking Lung Syndrome (SLS)
Introduction
Presentation
Diagnosis
Treatment
Prognosis
7.6.1.12 Associated Lung Disorders
Adult Respiratory Distress Syndrome (ARDS)
Infectious Complications
Pneumocystis Pneumonia (PCP) Prophylaxis
Lung Cancer
Drug Reactions
7.7 Rheumatoid Arthritis (RA)
7.7.1 Introduction
7.7.1.1 Introduction
7.7.1.2 Presentation
7.7.1.3 Diagnosis
7.7.1.4 Treatment
7.7.1.5 Prognosis
7.7.2 Pleural Diseases
7.7.2.1 Pleural Effusion
Introduction
Presentation
Diagnosis
Treatment
Complications
7.7.3 Pulmonary Vascular Diseases
7.7.3.1 PAH
7.7.3.2 DAH
7.7.4 Airway Diseases: Upper Airway Diseases
7.7.4.1 Cricoarytenoid Arthritis
Introduction
Presentation
Diagnosis
Treatment
Prognosis
7.7.4.2 Vocal Cord Rheumatoid Nodule
7.7.5 Airway Diseases: Lower Airway Diseases
7.7.5.1 Bronchiectasis
7.7.6 Airway Obstruction and Bronchial Hyperreactivity
7.7.6.1 Bronchiolitis Obliterans (BO)
Introduction
Presentation
Diagnosis
Treatment
Prognosis
7.7.6.2 Follicular Bronchiolitis
Introduction
Presentation
Diagnosis
Treatment
Prognosis
7.7.7 Rheumatoid Nodule and its Complications: (Necrobiotic Nodule)
7.7.7.1 Rheumatoid Nodule
Introduction
Presentation
Diagnosis
Treatment
Rheumatoid Nodulosis
7.7.7.2 Caplan Syndrome (Rheumatoid Pneumoconiosis)
Introduction
Presentation
Diagnosis
Treatment
Prognosis
7.7.8 Infections
7.7.8.1 Background
7.7.8.2 Latent Tuberculosis Infection (LTBI) Screening [129]
7.7.8.3 Cancer
7.7.8.4 Myopathy and Muscle Weakness
Introduction
Diagnosis
7.7.8.5 Fibrobullous Disease
7.7.8.6 Amyloidosis
7.8 Sjogren Syndrome (SS)
7.8.1 Background
7.8.2 Epistaxis
7.8.3 Hoarseness of the Voice
7.8.4 Xerotrachea and Xerobronchitis
7.8.5 Lower Airway Disease
7.8.5.1 Follicular Bronchiolitis (FB)
Introduction
Investigation
Treatment
Prognosis
7.8.6 Chronic Obstructive Pulmonary Disease (COPD)
7.8.7 Lung Parenchyma
7.8.7.1 ILD
Introduction
Subtypes
NSIP
Lymphocytic interstitial pneumonia (LIP)
7.8.8 Pleural Involvement
7.8.8.1 Pleural Effusion
7.8.9 Pulmonary Vascular Disease
7.8.9.1 PAH
Introduction
7.8.10 Cancer
7.8.10.1 Lymphoma
Introduction
Presentation
Diagnosis
Pseudolymphoma
Amyloidosis
7.9 Mixed Connective Tissue Disease (MCTD)
7.9.1 Introduction
7.9.2 Pulmonary Manifestations
7.9.2.1 Lung Parenchyma
Interstitial Lung Disease (ILD)
Introduction
Presentations
Diagnosis
Treatment
Prognosis
Alveolar Hemorrhage
Pulmonary Vascular Disease
PAH
Pleural Diseases
Pleural Effusion
7.10 Polymyositis (PM)/Dermatomyositis (DM)
7.10.1 Introduction
7.10.2 Pulmonary Manifestations
7.10.2.1 Parenchymal Lung Disease
Interstitial Lung Disease (ILD)
Introduction
Presentations
Diagnosis
Treatment
Prognosis
7.10.2.2 Aspiration Pneumonia
7.10.2.3 Pulmonary Vascular Disease
PAH
7.10.3 Pneumothorax (PNX) and Pneumomediastinum and Subcutaneous Emphysema
7.10.3.1 Introduction
7.10.4 Respiratory Failure and Hypoventilation
7.10.4.1 Introduction
7.10.4.2 Diagnosis
7.10.4.3 Complications
7.10.4.4 Treatment
7.10.4.5 Lung Cancer
References
8: Nervous System and Rheumatology
8.1 Introduction
8.1.1 Specific Objectives
8.2 Systemic Lupus Erythematosus (SLE)
8.2.1 Headache
8.2.1.1 Approach
8.2.2 Stroke
8.2.3 Seizure
8.2.3.1 Tips in History
8.2.4 Myelopathy
8.3 Rheumatoid Arthritis
8.3.1 Atlantoaxial Subluxation
8.3.2 Neuropathy
8.4 Neuropathy with Skin Rash
8.4.1 Tips in History and Physical Examinations
8.4.2 Laboratory Investigations and Imaging Modalities
8.4.3 Treatment
References
9: Diagnostic Approach to Proximal Myopathy
9.1 Introduction
9.1.1 Objectives
9.2 Clinical Presentation of Proximal Myopathy
9.2.1 History
9.2.2 Physical Examination
9.3 Differential Diagnosis of Proximal Myopathy
9.3.1 Toxins- and Drug-Induced Myopathy
9.3.2 Endocrine Myopathy
9.3.3 Dystrophic Myopathies
9.3.4 Inflammatory Myopathies
9.3.5 Myopathy Due to Infectious Disease
9.4 Diagnostic Approach
9.4.1 Muscle Enzyme
9.4.2 Rhabdomyolysis
9.4.3 Other Tests
9.4.4 Electromyography (EMG)
9.4.5 Muscle Magnetic Resonance Imaging (MRI)
9.4.6 Muscle Biopsy
9.4.7 Screening for Malignancy
9.4.8 Genetic Testing
9.5 The Management of Myopathy
9.5.1 Inherited Myopathy
9.5.2 Acquired Myopathy
References
10: Bones and Rheumatology
10.1 Introduction
10.2 Objectives
10.3 Bone Structures
10.4 Bone Remodeling and Bone Cells
10.4.1 Bone Cells
10.4.2 The Remodeling Cycle
10.4.3 Factors Influencing Remodeling
10.4.4 RANK/RANKL/OPG System
10.5 Mediators of Bone Loss in Rheumatic Diseases
10.5.1 Effects of Systemic Inflammation
10.5.1.1 Role of pro-Inflammatory Cytokines
10.5.1.2 Role of Inflammatory Cells
10.5.1.3 Causes of Uncoupling Process
The Wnt Signaling and its Antagonist, DKK1
Alteration of Glucocorticoid Signaling
10.5.2 Effects of Immobility
10.5.3 Effects of Glucocorticoids
10.6 Common Bone Diseases Associated with Rheumatic Disease
10.6.1 Rheumatoid Arthritis and Bone Loss
10.6.1.1 Predisposing Factor of Osteoporosis in RA
10.6.1.2 Pathological Process
10.6.1.3 Management of Bone Loss in RA
10.6.2 Systemic Lupus Erythematosus and Bone Loss
10.6.2.1 Predisposing Factors of Bone Loss in SLE
10.6.2.2 Pathological Process
10.6.2.3 Management of Bone Loss in SLE
10.6.3 Ankylosing Spondylitis and Bone Loss
10.6.3.1 Fracture Risk in AS
10.6.3.2 Management of Bone Loss in AS
10.6.4 Glucocorticoid-Induced Osteoporosis (GIOP)
10.6.4.1 Impact of GIOP
10.6.4.2 Approaching Managements of Patients with GIOP
10.6.4.3 Recommendations for Fracture Risk Assessment and Reassessment of Patient with GIOP
10.6.4.4 Recommendations for Initial Treatment and Prevention of GIOP
10.6.4.5 Rationale of Pharmacotherapy of GIOP
10.6.4.6 Follow-up Treatment Recommendations
10.7 Summary
References
11: Fever and Rheumatology
11.1 Introduction
11.2 Fever of Unknown Origin (FUO)
11.2.1 Definition [28]
11.2.2 Epidemiology
11.2.3 General Principles in the Treatment of FUO (Table 11.2)
11.2.4 Tips in FUO
11.3 Fever and Rheumatology
11.3.1 Introduction
11.4 Fever in Rheumatology Patient
11.4.1 History
11.4.2 Physical Examination (Table 11.3)
11.5 Rheumatologic Manifestation of Infectious Diseases
11.5.1 Introduction
11.5.1.1 Hepatitis B Virus Arthritis [104]
11.5.1.2 Acute Hepatitis B and Arthritis
11.5.1.3 Chronic Active Hepatitis B
11.5.1.4 Polyarteritis Nodosa
11.5.1.5 Essential Mixed Cryoglobulinemia
11.5.2 Hepatitis C Virus Arthritis
11.5.3 Parvovirus B19 Arthropathy
11.5.4 Dengue Virus
11.5.5 Septic Arthritis
11.5.6 Poncet’s Disease (Reactive Arthritis Associated with Tuberculosis) [121]
11.6 Vaccination in Adult Patient with Autoimmune Inflammatory Rheumatic Diseases (AIIRD)
11.6.1 Introduction
11.6.2 General Rules
References
12: Thrombosis in Rheumatological Diseases
12.1 Introduction
12.2 Pathophysiology of Thrombosis in Rheumatic Disorders
12.2.1 SLE and Thrombosis
12.2.1.1 Risk Factor and Etiology of Thrombosis in SLE
Inflammation and Disease Activity
Antiphospholipid (aPL) Antibodies
Protein C and S and Antithrombin Deficiencies
Factor V Leiden
Hyperhomocysteinemia
Traditional Risk Factors
12.2.1.2 Medication and Thrombosis in SLE
12.2.2 RA and Thrombosis
12.2.2.1 Risk Factor and Etiology of Thrombosis in RA
Lifestyle in RA
Inflammation
High Disease Activity and High Levels of Inflammatory Markers
Hospitalization
aPL Antibodies
TNF-α
Fibrinogen, VWF, Tissue Plasminogen Activator (t-PA) Antigen, and D-Dimer
Leukocytosis, Thrombocytosis, Increasing Platelet Activity, and Low Serum Albumin
High Systolic Blood Pressure (SBP) and Low Levels of High Density Lipoprotein (HDL)
Rheumatoid Factor (RF)
Prothrombotic Condition in RA
12.2.2.2 Medications and Thrombosis in RA
12.2.3 Vasculitis and Thrombosis
12.2.3.1 Large Vessel Vasculitis
12.2.3.2 Medium Vessel Vasculitis
12.2.3.3 Small Vessel Vasculitis
12.2.3.4 Risk Factors for Thrombosis in Vasculitis
Changes in Endothelial Function and Hypercoagulability
Hypercoagulability
Hypereosinophilia in Churg-Strauss
aPL Autoantibodies
12.2.3.5 Medications and Thrombosis in Vasculitis
12.2.4 Behçet’s Disease (BD)
12.2.4.1 Risk Factors for Thrombosis in BD
Endothelial Cell Dysfunction
Low Protein C
Activated Platelets and Microparticles (MP)
Vascular Endothelial Growth Factor (VEGF)
HLA-B51 and HLA-B35 Positivity
12.2.4.2 Medications and Thrombosis in BD
12.2.5 Antiphospholipid Syndrome (APS) and Thrombosis
12.2.5.1 Risk Factors for Thrombosis in APS
aPL Autoantibodies
The Effects of aPL Antibodies on Endothelial Cells
Hypercoagulable Effect of aPL Antibodies
Platelet Activation and Aggregation by aPL
β2GPI Binding with Platelet Factor 4 (PF4)
Activation of Monocytes by aPL Antibodies
Other Risk Factors for Thrombosis in APS
12.3 Approach and Diagnosis of Thrombosis in Rheumatic Diseases
12.3.1 History Taking
12.3.2 Physical Examination
12.3.3 Clinical Pretest Probability (CPTP) for VTE
12.3.4 Laboratory and Radiology Workup
12.4 Management of Thrombosis in Rheumatic Diseases, Prophylaxis, and Secondary Prevention of Thrombosis
12.4.1 Management of Thrombosis in Rheumatic Diseases
12.4.1.1 Special Consideration for Thrombosis in Rheumatic Disorders
12.4.2 Prophylaxis and Secondary Thrombosis Prevention in Rheumatic Disorders
12.4.2.1 Primary Prophylaxis in SLE Patients
12.4.2.2 Primary Prophylaxis in APS Patients
12.4.2.3 Primary Prophylaxis in High-Risk Situations
12.4.2.4 Secondary Prophylaxis in Patients with Positive aPL Antibodies
12.4.2.5 Refractory and Difficult Situations in aPL-Positive Patients
12.4.2.6 Statin Role for the Prophylaxis against Thrombosis in Rheumatic Diseases
References
13: The Blood in Rheumatology
13.1 Introduction
13.2 Objectives
13.3 Hematological Manifestations of Rheumatoid Arthritis (RA)
13.3.1 Introduction
13.3.1.1 Anemia
Anemia of Chronic Disease (ACD)
Iron Deficiency Anemia (IDA)
Macrocytic Anemia
Hemolytic Anemia
Bone Marrow Hypoplasia with Anemia
Pure Red Cell Aplasia
Treatment of Anemia in RA
13.3.1.2 White Blood Cell (WBC) Count Abnormalities
Neutropenia and Felty’s Syndrome
Leukocytosis
Eosinophilia
13.3.1.3 Platelet Abnormalities
13.3.1.4 Hematological Malignancies in RA
13.4 Hematological Manifestations of Systemic Lupus Erythematosus (SLE)
13.4.1 Introduction
13.4.1.1 Anemia
Anemia of Chronic Disease
13.4.2 Treatment
13.4.2.1 Iron Deficiency Anemia (IDA)
13.4.2.2 Autoimmune Hemolytic Anemia (AIHA)
13.4.2.3 Red Cell Aplasia
13.4.2.4 Microangiopathic Hemolytic Anemia (MAHA)
13.4.3 WBC Abnormalities
13.4.3.1 Leucopenia and Neutropenia
13.4.3.2 Lymphocytopenia
13.4.3.3 Decreased Eosinophils and Basophils
13.4.3.4 Treatment of Leukopenia
13.4.3.5 Leukocytosis
13.4.4 Platelet Abnormalities
13.4.4.1 Thrombocytosis
13.4.5 Pancytopenia
13.4.6 Lymphadenopathy and Splenomegaly
13.4.7 Antibodies to Clotting Factor and Phospholipids
13.5 Macrophage Activation Syndrome (MAS)
13.5.1 Introduction
13.5.1.1 Pancytopenia
13.5.1.2 Hepatosplenomegaly
13.5.1.3 Hyperferritinemia
13.5.1.4 Coagulopathy
13.5.2 Treatment
References
14: Renal System and Rheumatology
14.1 Introduction
14.2 Objectives
14.3 Proteinuria
14.4 Hematuria
14.5 Renal Involvement in Different Rheumatic Diseases
14.6 Lupus Nephritis (LN)
14.6.1 Diagnostic Criteria
14.6.2 Treatment
14.6.3 Adjunctive Treatments
14.7 Sjögren’s Syndrome
14.8 Cryoglobulinemic Syndrome (CG)
14.9 Scleroderma
14.9.1 Rheumatoid Arthritis (RA)
14.9.2 Renal Involvement in Vasculitis
14.9.2.1 Polyarteritis Nodosa (PAN)
14.9.3 Eosinophilic Granulomatosis with Polyangiitis EGPA (Churg-Strauss)
14.9.4 Granulomatosis with Polyangiitis GPA (Wegener’s) and Microscopic Polyangiitis (MPA)
14.9.5 Henoch-Schönlein Purpura (HSP) (IgA Vasculitis)
14.9.6 Renal Side Effects of DMARDs and NSAIDs
References
15: Skin Manifestations of Rheumatological Diseases
15.1 Introduction
15.2 Objectives
15.3 Polyarthritis with Skin: (Diagram 15.1)
15.3.1 Rheumatoid Arthritis (RA)
15.3.2 Pyoderma Gangrenosum
15.3.3 Rheumatoid Vasculitis
15.3.4 Rheumatoid Nodule
15.3.5 Skin Ulceration
15.3.6 Systemic Lupus Erythematosus (SLE)
15.3.7 ACLE (Localized)
15.3.7.1 Malar Rash
15.3.7.2 Disseminated (Generalized) ACLE
15.3.7.3 SCLE
15.3.7.4 CCLE
15.3.8 Others
15.3.8.1 Photosensitivity
15.3.8.2 Discoid Rash
15.3.8.3 Alopecia
15.3.8.4 Oral Ulcer
15.3.8.5 Systemic Sclerosis “Scleroderma”
15.3.8.6 Raynaud Phenomenon
15.3.9 Telangiectasia
15.3.10 Sclerodactyly
15.3.11 Cutaneous Sclerosis
15.3.12 Digital Ulcers
15.3.13 Calcinosis Cutis
15.4 Psoriasis
15.4.1 Scales (Fig. 15.9)
15.4.1.1 Nail Involvement
15.4.1.2 Erythroderma
15.4.1.3 Guttate Lesion
15.4.1.4 Psoriatic Arthritis
15.4.2 Dermatomyositis (DM)
15.4.2.1 Gottron’s Papules
15.4.2.2 Heliotrope Eruption
15.4.3 Facial Erythema
15.4.4 Photodistributed Poikiloderma
15.4.5 Periungual Abnormalities
15.4.6 Psoriasiform Changes in Scalp
15.4.7 Calcinosis Cutis
15.4.8 Reactive Arthritis
15.4.8.1 Circinate Balanitis
15.4.8.2 Keratoderma
15.4.9 Hepatitis C Virus (HCV)
15.4.9.1 Porphyria Cutanea Tarda
15.4.9.2 Leukocytoclastic Vasculitis
15.4.10 Lichen Planus
15.4.11 Necrolytic Acral Erythema
15.4.12 Polyarteritis Nodosa
15.4.12.1 Livedo Reticularis
15.4.12.2 Ulcerations
15.4.13 Digital Ischemia
15.5 Sarcoidosis
15.5.1 Erythema Nodosum
15.5.2 Papular Sarcoidosis
15.5.3 Nodular Sarcoidosis
15.5.4 Maculopapular Sarcoidosis
15.5.5 Plaque Sarcoidosis
15.5.6 Lupus Pernio
15.5.7 Hypopigmented Sarcoidosis
15.5.8 Atrophic and Ulcerative Sarcoidosis
15.6 Rheumatic Fever
15.6.1 Arthritis
15.6.2 Erythema Marginatum
15.6.3 Subcutaneous Nodules
15.7 Behçet’s Disease
15.7.1 Erythema Nodosum-like Lesion
15.7.2 Acneiform Lesion
15.7.3 Folliculitis-like Rash
15.7.4 Papulopustular Eruptions
15.7.5 Erythema Multiforme-like Lesions
15.7.6 Superficial Thrombophlebitis
15.7.7 Ulcers (Oral, Genital)
15.7.8 Pyoderma Gangrenosum
15.7.9 Positive Pathergy Reaction at Injection Site
15.7.10 Arthritis
15.8 Inflammatory Bowel Disease
15.8.1 Erythema Nodosum (EN)
15.8.2 Pyoderma Gangrenosum
15.8.3 Oral Ulcer
15.8.4 Musculoskeletal Manifestations
15.8.5 Arthritis
15.9 Severe and Life-Threatening Conditions (Fig. 15.21)
15.10 Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN)
15.10.1 Rash
15.10.2 Bullous Lesions
15.10.3 Urticarial Lesions (Not Pruritic)
15.10.4 Erythema
15.10.5 Palpable Purpura
15.10.6 Edema (Face, Tongue)
15.10.6.1 Sloughing of Skin
15.11 Erythroderma Exfoliation
15.11.1 Erythema
15.11.1.1 Exfoliation and Scales (2–6 Days after Erythema)
15.11.2 Pruritus
15.11.3 Pain
15.11.4 Dyspigmentation
15.11.5 Palmoplantar Keratoderma
15.11.6 Nail Changes
15.11.7 Diffuse Non-scarring Alopecia
15.11.8 Systemic Manifestation
15.11.9 Complications
15.12 Gonococcal Arthritis
References
16: Cardiovascular Diseases and Rheumatology
16.1 Introduction
16.2 Cardiovascular Manifestations in the Rheumatic Diseases
16.2.1 Rheumatoid Arthritis (RA)
16.2.1.1 Pericarditis
16.2.1.2 Myocardial Involvement
Antimalarials-Induced Cardiotoxicity
16.2.1.3 Heart Failure
16.2.1.4 Coronary Artery Disease (CAD)
16.2.1.5 Rheumatoid Nodule
16.2.2 SLE
16.2.2.1 Pericarditis
16.2.2.2 Myocarditis
16.2.2.3 Coronary Artery Disease (CAD)
16.2.2.4 Endocarditis (Libman–Sacks Endocarditis)
16.2.3 Systemic Sclerosis (SSc)
16.2.3.1 Myocardial Fibrosis
16.2.3.2 Myocardial Ischemia
16.2.3.3 Pericarditis
16.2.4 Antiphospholipid Syndrome
16.2.4.1 Aspirin and APS
16.2.5 Ankylosing Spondylitis (AS)
16.2.5.1 Aortic Involvement
16.2.5.2 Myocardial Involvement
16.2.5.3 Conduction Abnormalities
16.2.6 Psoriatic Arthritis
16.2.6.1 Arrhythmias
16.2.6.2 CAD:
16.2.7 Systemic Vasculitis
16.3 The Accelerated Atherosclerosis Effects on CAD in Rheumatologic Diseases
16.4 Metabolic Syndrome and Rheumatological Diseases
16.4.1 RA
16.4.2 SLE
16.4.3 AS
16.4.4 Psoriasis
16.4.5 Gout
16.5 The Various Medications that Are Being Used in the Management of Rheumatologic Disease that Have Variable Effects on CAD
16.5.1 NSAIDs
16.5.2 Glucocorticoids (GC)
16.5.3 Methotrexate
16.5.4 TNF Biologic DMARDs
16.5.5 Non-TNF Biologic DMARDs
Appendix 1
References
17: Gestational Rheumatology
17.1 Introduction
17.2 Objectives
17.3 Physiology of Pregnancy
17.3.1 Changes in Cardiovascular System
17.3.2 Hematological Changes
17.3.3 Changes in Coagulation System
17.3.4 Changes in the Maternal Immune System
17.3.5 Changes in the Endocrine Glands
17.4 Systemic Lupus Erythematosus
17.4.1 Introduction
17.4.2 Influence of Pregnancy on SLE
17.4.3 Lupus Flares
17.4.4 Lupus Nephritis (LN)
17.4.5 Influence of SLE on Pregnancy
17.4.6 Hypercoagulability in SLE
17.4.6.1 Platelet Activation
17.4.6.2 Lupus Platelets
17.4.6.3 Laboratory Workup
17.4.6.4 High-Risk Clinical Scenarios
17.4.6.5 Management of Lupus Pregnancy
A) Management Issues
B) Treatment of Active Lupus Activity
C) Delivery
D) Puerperium
17.5 Antiphospholipid Syndrome in Pregnancy
17.5.1 Introduction
17.5.2 Diagnostic Criteria
17.5.3 Pathogenesis of APS
17.5.3.1 Thrombosis (Thrombosis of Vessels and Placenta)
17.5.3.2 Defective Placentation
17.5.3.3 Inflammation
17.5.4 Treatment
17.5.4.1 Low-Dose ASA (LDA): Either Alone or Combined with Heparin
17.5.4.2 Aspirin/Heparin-Resistant APS (AHR-APS)
17.5.5 Conclusion
17.6 Neonatal Lupus Erythematosus
17.6.1 Introduction
17.6.2 Pathogenesis and Clinical Features
17.6.3 Treatment of Congenital Heart Block
17.6.4 Conclusion
17.7 Rheumatoid Arthritis (RA) and Pregnancy
17.7.1 Introduction
17.7.2 Effect of Pregnancy on RA
17.7.3 Effects of RA on Pregnancy
17.8 Sjogren’s Syndrome (SS) and Pregnancy
17.9 Systemic Sclerosis (SSc) and Pregnancy
17.10 Vasculitis and Pregnancy
17.10.1 Introduction
17.10.2 Large Vessel Vasculitis
17.10.2.1 Behcet’s Disease (BD)
17.10.2.2 Takayasu’s Arteritis
17.10.3 Medium Vessels Vasculitis
17.10.3.1 Polyarteritis Nodosa (PAN)
17.10.4 Small Vessels Vasculitis
17.10.4.1 Granulomatosis with Polyangiitis (GPA) (Wegner’s Granulomatosis)
17.10.4.2 Eosinophilic Granulomatosis with Polyangiitis (Churg-Strauss Syndrome)
17.11 Polymyositis (PM)/Dermatomyositis (DM) and Pregnancy
17.12 Spondyloarthritis and Pregnancy
17.13 Conclusion
References
18: Perioperative Management of Patients with Rheumatic Diseases
18.1 Introduction
18.1.1 Objectives
18.2 The Preoperative Medical Evaluation
18.2.1 History Taking
18.2.2 Physical Examination
18.2.3 Investigations
18.2.4 Assessment of Specific Clinical Problems in Patients with RA
18.2.4.1 Cardiovascular
18.2.4.2 Pulmonary
18.2.4.3 Cricoarytenoid Arthritis
18.3 Perioperative Drug Management
18.3.1 Perioperative Management if Antirheumatic Drugs [12–16]
18.3.2 Perioperative Management of Other Systemic Medications [12–14, 16, 17]
18.3.3 DVT Prophylaxis
18.3.4 Prophylactic Antibiotics [20, 29]
18.4 Assessment of Specific Clinical Problems in Patients with SLE
18.5 Postoperative Follow-Up
18.6 Patient Education
18.7 Physical Activity and Rehabilitation
References
19: Eye and Rheumatology
19.1 Introduction
19.1.1 Objectives
19.2 Uveitis
19.2.1 Approach to Uveitis
19.2.1.1 History
19.2.1.2 Eye Examination
19.2.1.3 Treatment
19.3 Eye Dryness
19.3.1 Approach to Dry Eye
19.3.1.1 History
19.3.1.2 Eye Examination
19.3.1.3 Treatment
19.4 Corneal Ulcer
19.4.1 Approach to Corneal Ulcer
19.4.1.1 History
19.4.1.2 Eye Examination
19.4.1.3 Treatment
19.5 Scleritis
19.5.1 Approach to Scleritis
19.5.1.1 History
19.5.1.2 Eye Examination
19.5.1.3 Treatment
19.6 Episcleritis
19.6.1 Approach to Episcleritis
19.6.1.1 History
19.6.1.2 Eye Examination
19.6.1.3 Treatment
19.7 Cataract
19.7.1 Approach to Cataract
19.7.1.1 History
19.7.1.2 Eye Examination
19.7.1.3 Treatment
19.8 Glaucoma
19.8.1 Approach to Glaucoma
19.8.1.1 History
19.8.1.2 Eye Examination
19.8.1.3 Treatment
19.9 Ophthalmologic Side Effects of Rheumatic Medications [17]
19.10 Antimalarial-Related Retinopathy
19.10.1 Approach to Antimalarial-Related Retinopathy
19.10.1.1 History
19.10.1.2 Eye Examination
19.10.1.3 Treatment
References
20: Vasculitis and Rheumatology
20.1 Learning Objectives
20.1.1 Pathologic Mechanisms Underlying Vasculitis
20.1.2 Classification of Vasculitis
20.1.3 The 2012 Chapel Hill Consensus Conference (CHCC) on Nomenclature of Vasculitis
20.1.4 How to Approach a Patient with Vasculitis?
20.1.4.1 A Case Scenario
20.1.5 Major Forms of Vasculitis
20.1.5.1 Takayasu’s Arteritis (TA)
20.1.5.2 Giant Cell Arteritis (GCA)
20.1.5.3 Polyarteritis Nodosa (PAN)
20.1.5.4 Granulomatosis with Polyangiitis (GPA) and Microscopic Polyangiitis (MPA)
20.1.5.5 Eosinophilic Granulomatosis with Polyangiitis (EGPA)
20.1.5.6 IgA Vasculitis (IgAV)
20.1.5.7 Cutaneous Leukocytoclastic Angiitis
20.1.5.8 Behcet’s Disease (BD)
References
21: Diabetes and Rheumatology
21.1 Introduction
21.1.1 Objectives
21.2 Pathophysiology
21.2.1 Classification of Rheumatological Manifestations in Diabetic Patients
21.3 Carpal Tunnel Syndrome
21.3.1 Epidemiology
21.3.2 Approach to CTS
21.3.2.1 History
21.3.2.2 Physical Examination
21.3.2.3 Investigations
21.3.3 Treatment
21.4 Reflex Sympathetic Dystrophy
21.4.1 Pathogenesis
21.4.2 Epidemiology
21.4.3 Approach to RSD
21.4.3.1 History
21.4.3.2 Physical Examination
21.4.4 Diagnosis Criteria (Table. 21.2)
21.4.5 Treatment
21.5 Flexor Tenosynovitis
21.5.1 Pathogenesis
21.5.2 Epidemiology
21.5.3 Approach to Flexor Tenosynovitis
21.5.3.1 History
21.5.3.2 Physical Examination
21.5.3.3 Investigations
21.5.4 Treatment [17]
21.6 Diabetic Muscular Infarction
21.6.1 Pathophysiology
21.6.2 Epidemiology
21.6.3 Approach to DMI
21.6.3.1 History
21.6.3.2 Physical Examination
21.6.3.3 Imaging Studies
21.6.3.4 Muscle Biopsy (for Confirmation)
21.6.4 Treatment
21.7 Adhesive Capsulitis (Frozen Shoulder)
21.7.1 Pathogenesis
21.7.2 Epidemiology
21.7.3 Approach to Frozen Shoulder
21.7.3.1 History
21.7.3.2 Physical Examination
21.7.3.3 Imaging
21.7.4 Treatment
21.8 Neuropathic Osteoarthropathy (Charcot Joint)
21.8.1 Pathogenesis
21.8.2 Epidemiology
21.8.3 Approach to Charcot Joint
21.8.3.1 History
21.8.3.2 Physical Examination
21.8.4 Treatment
21.9 Diabetes and Osteoporosis
21.9.1 Pathogenesis
21.9.2 Challenges in Diagnosing and Treating Diabetes-Related Osteoporosis
21.9.3 Approach to Diabetes-Related Osteoporosis
21.9.3.1 History
21.9.3.2 Physical Exam
21.9.3.3 Diagnosis
21.9.3.4 Management of Osteoporosis on Diabetic Patients
References
22: Soft Tissue Rheumatic Disorders
22.1 Introduction
22.1.1 Learning Objectives
22.1.2 Classification of Soft Tissue Disorders
22.1.3 Bursitis
22.1.4 Tendinitis
22.1.5 Rotator Cuff Tendinitis and Rotator Cuff Tear
22.1.6 Enthesitis
22.1.7 Achilles Tendinitis
22.1.8 Epicondylitis [26, 27]
22.1.9 Fasciitis
22.1.10 Plantar Fasciitis
22.1.11 Palmar Fasciitis
22.1.12 Eosinophilic Fasciitis
References
23: Gastrointestinal Manifestations of Rheumatic Diseases
23.1 Objectives
23.2 Gastrointestinal Manifestations of Systemic Lupus Erythematosus (SLE)
23.2.1 Oral Cavity Manifestations of SLE
23.2.2 Esophageal Manifestations of SLE
23.2.3 Gastric Manifestations of SLE
23.2.4 Colonic and Small Bowel Manifestations of SLE
23.2.5 Pancreatic and Gallbladder Manifestations of SLE
23.2.6 Hepatic Manifestations of SLE
23.2.7 Gastrointestinal Malignancies in Systemic Lupus Erythematosus
23.3 Gastrointestinal Manifestations of Rheumatoid Arthritis (RA)
23.3.1 Dysphagia and Other Esophageal Manifestations of Rheumatoid Arthritis
23.3.2 Gastric Manifestations of Rheumatoid Arthritis
23.3.3 Intestinal and Colonic Manifestations of Rheumatoid Arthritis
23.3.4 Hepatic Manifestations of Rheumatoid Arthritis
23.3.5 Other Gastrointestinal Manifestations of Rheumatoid Arthritis
23.4 Gastrointestinal Manifestations of Inflammatory Myositis
23.4.1 Symptomatology
23.4.2 Esophageal Manifestations of Inflammatory Myositis
23.4.3 Gastric Manifestations of Inflammatory Myositis
23.4.4 Intestinal Manifestations of Inflammatory Myositis
23.4.5 Hepatic Manifestations of Inflammatory Myositis
23.5 Gastrointestinal Manifestations of Systemic Sclerosis
23.5.1 Esophageal Manifestations of Systemic Sclerosis
23.5.2 Gastric Manifestations of Systemic Sclerosis (SSc)
23.5.3 Intestinal Manifestations of Systemic Sclerosis
23.5.4 Colonic and Anorectal Manifestations of Systemic Sclerosis
23.6 Gastrointestinal Manifestations of Behcet’s Disease (BD)
23.6.1 Esophageal Manifestations of Behçet’s Disease
23.6.2 Gastric Manifestations of Behçet’s Disease
23.6.3 Intestinal and Colonic Manifestations of Behcet’s Disease
23.6.4 Pancreatic Manifestations of Behcet’s Disease
23.6.5 Hepatic Manifestations of Behcet’s Disease
23.6.6 Visceral Arterial Involvement in Patients with Behcet’s Disease
23.7 Gastrointestinal Manifestations of Vasculitis
23.7.1 Polyarteritis Nodosa (PAN)
23.7.1.1 Gastrointestinal Manifestations of Polyarteritis Nodosa
23.7.1.2 Hepatic and Biliary Manifestations of Polyarteritis Nodosa
23.7.1.3 Pancreatic Manifestations of Polyarteritis Nodosa
Diagnostic Modalities of Polyarteritis Nodosa
Treatment
23.7.2 Granulomatosis with Polyangiitis—GPA (Formerly Named Wegener’s Granulomatosis)
23.7.3 Eosinophilic Granulomatosis with Polyangiitis—EGPA (Formerly Named Churg-Strauss Syndrome)
23.7.4 Henoch-Schonlein Purpura (HSP)
23.7.5 Behcet’s Disease
23.8 Gastrointestinal Manifestations of Spondyloarthropathies (SpA)
23.8.1 Ankylosing Spondylitis (AS)
23.8.2 Psoriatic Arthritis (PsA)
23.8.3 Reactive Arthritis
23.8.4 IBD-Associated SpA
23.9 Gastrointestinal Manifestations of Sjogren’s Syndrome (SS)
23.9.1 Oral Manifestations of Sjogren’s Syndrome
23.9.2 Esophageal Manifestations of Sjogren’s Syndrome
23.9.3 Gastric Manifestations of Sjogren’s Syndrome
23.9.4 Bowel and Colonic Manifestations of Sjogren’s Syndrome
23.9.5 Pancreatic Manifestations of Sjogren’s Syndrome
23.9.6 Hepatic Manifestations of Sjogren’s Syndrome
References
24: Pediatric Rheumatology
24.1 Introduction
24.2 Learning Objectives
24.3 Pediatric Rheumatic Diseases
24.4 Childhood Onset SLE
24.5 Juvenile Dermatomyositis
24.6 Juvenile Idiopathic Arthritis
24.7 Childhood Vasculitis
24.8 Kawasaki Disease
24.9 Autoinflammatory Syndromes
References
Part III: Classification Criteria and Guidelines
25: Classification Criteria and Clinical Practice Guidelines for Rheumatic Diseases
25.1 Introduction
25.2 Rheumatoid Arthritis Classification Criteria and Management Guidelines
25.2.1 Classification Criteria (Fig. 25.1)
25.2.2 Management Guidelines [2] (Fig. 25.2)
25.3 Systemic Lupus Erythematosus Classification Criteria and Management Guidelines
25.3.1 Classification Criteria of Systemic Lupus Erythematosus (Fig. 25.3)
25.3.2 Management Guidelines for Systemic Lupus Erythematosus
25.3.2.1 General Management Recommendations
25.3.2.2 Lupus Nephritis (LN)
25.3.2.3 Neuropsychiatric Lupus [10]
25.4 Antiphospholipid Syndrome Classification Criteria and Management Guidelines
25.4.1 Classification Criteria
25.4.2 Management Guidelines
25.5 Vasculitis Classification Criteria and Management Guidelines
25.5.1 Classification Criteria (Fig. 25.18)
25.5.2 Management Guidelines
25.5.3 Classification Criteria [18]
25.6 Spondyloarthritis Classification Criteria and Management Guidelines
25.6.1 Classification Criteria (Figs. 25.20, 25.21 and 25.22) (Table 25.3)
25.6.2 Management Guidelines
25.7 Psoriatic Arthritis Classification Criteria and Management Guidelines (Table 25.4) (Fig. 25.25)
25.7.1 Classification Criteria
25.7.2 Management Guidelines
25.8 Systemic Sclerosis Classification Criteria and Management Guidelines
25.8.1 Classification Criteria of Systemic Sclerosis (Tables 25.5, 25.6 and 25.7)
25.8.2 Management Guidelines of Systemic Sclerosis (Table 25.8)
25.8.3 Dermatomyositis and Polymyositis Classification Criteria and Management Guideline
25.8.4 Summary of Polymyositis and Dermatomyositis Classification Criteria [27] (Fig. 25.27)
25.8.5 Sjögren’s Syndrome Classification Criteria and Management Guidelines (Table 25.9)
25.8.6 Behcet’s Disease Classification Criteria and Management Guidelines
25.8.7 Diagnostic Criteria for Behcet’s Disease, International Study Group for Behcet’s Disease (1990) (Tables 25.10 and 25.11)
25.8.8 Gout Classification Criteria and Management Guidelines [31] (Box 25.2)
25.9 Osteoarthritis Classification Criteria and Management Guidelines
25.9.1 Classification Criteria (Fig. 25.28)
25.9.2 Osteoarthritis Management Guidelines [35] (Figs. 25.29, 25.30 and 25.31)
25.9.2.1 Osteoporosis Classification Criteria and Management Guidelines [36–41] (Table 25.12) (Box 25.3) (Fig. 25.32)
References

Citation preview

Skills in Rheumatology Hani Almoallim Mohamed Cheikh Editors

Skills in Rheumatology

Hani Almoallim  •  Mohamed Cheikh Editors

Skills in Rheumatology

Editors Hani Almoallim Department of Medicine College of Medicine, Umm Al-Qura University (UQU) Makkah Saudi Arabia

Mohamed Cheikh Department of Medicine Doctor Soliman Fakeeh Hospital Jeddah Saudi Arabia

This book is an open access publication. ISBN 978-981-15-8322-3    ISBN 978-981-15-8323-0 (eBook) https://doi.org/10.1007/978-981-15-8323-0 © The Editor(s) (if applicable) and The Author(s) 2021 Open Access  This book is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made. The images or other third party material in this book are included in the book's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the book's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Singapore Pte Ltd. The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore

To my father, who left the world after a lifetime of leaving smiles on the faces of those around him. His kindness knew no bounds, and whose presence sparked joy into those dealing with him. His love for life only equaled by his love for giving that was only limited by our ability to receive. I have no doubt that without him would not be who I am today. Hani Almoallim To my biggest fan, the greatest mother I could have asked for, and to all my family, who have been providing their support whenever I need it most. Mohamed Cheikh

Introduction

How to Use This Book? This is a book that deals with the daily practice of rheumatology! We did not write it just to make another book! It is not a book to be added to the list that already exists on the shelf! It is a small practical one, in which we rather focus on the skills that the physician, the patient, or caregiver might need to take care of rheumatologic complaints and diseases! Many junior staff start working in Rheumatology or see patients with arthritis may find themselves incompetent in basic skills while evaluating such patients. This book provides a comprehensive yet simple guide for junior or senior staff to deal with rheumatology patients. You do not need to read the whole book to get its benefits nor do you need to read it linearly. You just need to read the relevant section you are interested in. For example, if you just need to know how to examine the small joints of the hands, you can go directly to musculoskeletal (MSK) examination chapter: hands examination or if you need to know details about a biological drugs used in Rheumatology, you can go directly to the pharmacology chapter: biological drugs. In other words, you may determine in advance what you need to master each time you hold the book! The book consists of three parts. The first part is about basic skills in rheumatology. There is a comprehensive approach to history taking of patients with arthritis. We suggest this approach on the basis of differential diagnosis. Any patient with arthritis needs a comprehensive MSK examination, laboratory evaluation, pharmacological drugs analysis and radiological assessment. (You may just need to know what drugs are the patient taking especially if he/ she has an established diagnosis of arthritis?). We put special emphasis on low back pain, as there is a distinctive approach to this complaint. There is a significant delay that may reach 7–10 years before one can diagnose a patient with diseases characterized by inflammatory back pain like ankylosing spondylitis (AS). The second part of the book is designed to address common medical problems affecting patients with arthritis. It is truly said that to be good in rheumatology you need to be good in internal medicine! Rheumatologic diseases are systemic diseases affecting nearly all body systems. This comprehensive approach to common medical problems should emphasize the reader’s skills not only in Rheumatology but also in general internal medicine. A reader can approach this part at any point. If a systemic lupus erythematosus (SLE) patient vii

viii

Introduction

has anemia, there is a hematology chapter one can go to directly to; or if another SLE patient has headaches, stroke, and/or other neurological complaints, just read the chapter that deals with how to approach neurological complaints that contain elegant flow chart, tables, and diagnostic algorithms. There is also a chapter about pediatric Rheumatology highlighting the essential issues in dealing with rheumatic diseases in this young age group. The last part of the book is a compilation of recent recommendations for management guidelines and current classification criteria in Rheumatology. Lately, there has been a tremendous progress in the practice of Rheumatology worldwide. This has resulted in the introduction of new recommendations for the management and classification criteria. We tried to bring in this part all efforts that have been produced to enhance the practice of Rheumatology. However, if you need to read further details about the management of a particular disease beyond the guidelines, you would need to read from recent medical literature. To sum up: this book is a practical guide designed for building your skills in dealing with Rheumatology patients. We focus on diagnostic approaches to medical problems. You may find more than one style in the different chapters you are going to read. This is because each contributor thought about the best approach to deliver the contents. This may explain partly the variations in writing styles in some chapters. Dealing with a patient with a skin condition in rheumatology may not have the same approach as when dealing with a patient with shortness of breath. We offer variety of approaches to entertain the reader. We hope that medical students, interns, residents, fellows, general practitioners, and rheumatologists appreciate the efforts put into making this book a useful aid to deliver a better care for patients with arthritis. The objectives of this book are as follows: 1. To compose a comprehensive approach to managing patients with arthritis. 2. To perform MSK examinations for the most commonly involved joints in inflammatory arthritis. 3. To interpret autoantibodies in the appropriate clinical settings. 4. To discuss indications and contraindications of the most common drugs used in rheumatology practice. 5. To order appropriate imaging modality for assessing patients with rheumatic complaints. 6. To construct a diagnostic approach to common medical problems affecting patients with rheumatic diseases. 7. To review recent classification criteria and treatment recommendation guidelines in rheumatology. We hope you will enjoy reading this book. We welcome your comments and feedback. Makkah, Saudi Arabia Jeddah, Saudi Arabia

Hani Almoallim Mohammad Cheikh

Acknowledgement

This work is supervised by Alzaidi Chair of Research in Rheumatic Diseases (ZCRD), Umm Alqura University, Makkah, Saudi Arabia

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Contents

Part I Basics in Rheumatology 1 History-Taking Skills in Rheumatology����������������������������������������   3 Laila Alharbi and Hani Almoallim 2 Approach to Musculoskeletal Examination����������������������������������  17 Hani Almoallim, Doaa Kalantan, Laila Alharbi, and Khaled Albazli 3 Laboratory Interpretation of Rheumatic Diseases ����������������������  67 Altaf Abdulkhaliq and Manal Alotaibi 4 Pharmacotherapy in Systemic Rheumatic Diseases ��������������������  83 Layla Borham and Waleed Hafiz 5 Radiology in Rheumatology������������������������������������������������������������ 105 Nizar Al Nakshabandi, Ehab Joharji, and Hadeel El-Haddad Part II Diagnostic Approach to Common Medical Problems in Patients with Rheumatic Diseases 6 Low-Back Pain �������������������������������������������������������������������������������� 127 Khaled Albazli, Manal Alotaibi, and Hani Almoallim 7 Pulmonary Manifestations of Connective Tissue Diseases���������� 139 Rabab Taha and Maun Feteih 8 Nervous System and Rheumatology���������������������������������������������� 177 Emad Alkohtani and Amal Alkhotani 9 Diagnostic Approach to Proximal Myopathy�������������������������������� 191 Hani Almoallim, Hadiel Albar, and Fahtima Mehdawi 10 Bones and Rheumatology���������������������������������������������������������������� 209 Altaf Abdulkhaliq 11 Fever and Rheumatology���������������������������������������������������������������� 241 Mohamed Cheikh and Nezar Bahabri 12 Thrombosis in Rheumatological Diseases�������������������������������������� 263 Fozya Bashal

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13 The Blood in Rheumatology������������������������������������������������������������ 291 Nahid Janoudi and Ammar AlDabbagh 14 Renal System and Rheumatology �������������������������������������������������� 309 Sami Alobaidi, Manal Alotaibi, Noura Al-Zahrani, and Fahmi Al-Dhaheri 15 Skin Manifestations of Rheumatological Diseases������������������������ 329 Taha Habibullah, Ammar Habibullah, and Rehab Simsim 16 Cardiovascular Diseases and Rheumatology�������������������������������� 353 Rania Alhaj Ali, Hussein Halabi, and Hani Almoallim 17 Gestational Rheumatology�������������������������������������������������������������� 383 Hanan Al-Osaimi and Areej Althubiti 18 Perioperative Management of Patients with Rheumatic Diseases �������������������������������������������������������������������������������������������� 407 Manal Alotaibi, Khaled Albazli, Lina Bissar, and Hani Almoallim 19 Eye and Rheumatology�������������������������������������������������������������������� 419 Abdullah A Al-ghamdi 20 Vasculitis and Rheumatology���������������������������������������������������������� 429 Waleed Hafiz 21 Diabetes and Rheumatology������������������������������������������������������������ 445 Alaa Monjed 22 Soft Tissue Rheumatic Disorders���������������������������������������������������� 461 Roaa Mahroos and Hani Almoallim 23 Gastrointestinal Manifestations of Rheumatic Diseases�������������� 475 Hussein Halabi, Ammar AlDabbagh, and Amany Alamoudi 24 Pediatric Rheumatology������������������������������������������������������������������ 501 Reem Abdwani Part III Classification Criteria and Guidelines 25 Classification Criteria and Clinical Practice Guidelines for Rheumatic Diseases�������������������������������������������������������������������������� 521 Rola Hassan, Hanan Faruqui, Reem Alquraa, Ayman Eissa, Fatma Alshaiki, and Mohamed Cheikh

Contents

About the Editors

Hani  Almoallim has been a practicing rheumatologist for more than 17 years. He is a qualified educationalist and has been teaching rheumatology to undergraduate and postgraduate students since 2004. He has published over 80 papers on rheumatology, internal medicine, and medical education in peer-reviewed, international journals and on MedEdPORTAL (the official publication site for the American Association of Medical Colleges (AAMC)). He is the Chair Professor of Alzaidi Chair of Research in Rheumatic Diseases at Umm Alqura University and established the first data registry for rheumatoid arthritis in Saudi Arabia. He has conducted many educational workshops on early arthritis for trainees and general practitioners. He has observed and studied the reasons behind gaps in knowledge and skills among trainees in the practice of rheumatology. Mohamed Cheikh  is a consultant in internal medicine and a rheumatology fellow and has participated in several educational activities as well as research projects with Prof. Almoallim. He is actively involved in training young physicians to perform musculoskeletal system examinations.

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Part I Basics in Rheumatology

1

History-Taking Skills in Rheumatology Laila Alharbi and Hani Almoallim

1.1

Introduction

History taking in rheumatology is the most important skill needed for proper handling of a patient with a rheumatological complaint. Obtaining a good history will help you to reach almost 90% of your diagnosis. However, history taking is mostly depending on experience and practice rather than theoretical recall. Here in this section, we provide you with the most important points in history taking you should use while dealing with rheumatological patients. There is an approach to history taking in rheumatology started as with the classical approach in history taking like any other disease. There is much focus on rheumatological aspects related to the onset of joints pains, patterns, symmetry of joints involvement, number of joints involved, and ultimately rheumatology review of systems. We summarized the classic symptomatic correlations with certain rheumatological diseases. We present briefly a suggested approach to your presentation of the entire case.

L. Alharbi Medical College, Umm Al Qura university, Makkah, Saudi Arabia Department of Internal Medicine, Skåne University Hospital, Malmoe, Sweden H. Almoallim (*) Medical College, Umm Al-Qura University (UQU), Makkah, Saudi Arabia e-mail: [email protected] © The Author(s) 2021 H. Almoallim, M. Cheikh (eds.), Skills in Rheumatology, https://doi.org/10.1007/978-981-15-8323-0_1

1.1.1 Objectives 1. To compose a comprehensive and organize history for patients with rheumatological problems. 2. To recall the most important points in eliciting history for certain rheumatological diseases. 3. To construct a differential diagnosis in rheumatology. 4. To develop an approach for monitoring patients with arthritis.

1.2

Approach to History Taking in Rheumatology

This approach is based on the assumption that majority of patients with rheumatological diseases present at the beginning with joint(s) pain. Rheumatological diseases are systemic diseases affecting almost all body systems with no system that is preserved. You may have patients with neurological complaints (like hemiplegia because of ischemic stroke) end up with the diagnosis of a rheumatological disease like systemic lupus erythematosus (SLE) and secondary antiphospholipid syndrome (APS). Here the initial presentation was not joints pain, but yet the final diagnosis was rheumatological. This concept emphasizes the point that good foundations in general internal medicine is essential to the rheumatology practice. 3

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L. Alharbi and H. Almoallim

The approach to joints pain for any new patient should establish two basic issues: the personal data and then full analysis of the presenting illness. The latter includes the followings (Fig. 1.1).

9. Relieving and aggravating factors. 10. Rheumatology review of systems. This should be followed by the classical components in any history taking in internal medicine (past medical and surgical history, family history, drug and allergy, and social history). Here is a brief description about each one of the above.

1. Onset. 2. Duration. 3. Patterns of joints affected. 4. Symmetry. 5. Number of joints affected. 6. Associated symptoms. 7. Constitutional symptoms. 8. Functional impairment.

1. Onset: The patient should determine whether joint(s) pain have started suddenly or gradually. This is essential as the top differential diagnoses that should be ruled out for sudden

Ia- Classical approach for a new patient

A-Personal Identification

B-History of presenting illness (joints pain)

1-Onset (When did you first notice this problem) X

X

X

X

Gradual (weeks to months):

Sudden (hours to few days): - Septic arthritis (bacterial arthritis, viral arthritis (e.g. parvovirus 19 and rubella) - Acute rheumatic fever - Reactive arthritis - Crystal-induced arthritis - Elderly onset rheumatoid arthritis.

X

- Inflammatory arthritis like: rheumatoid arthritis (RA), psoriatic arthritis (PsA), reactive arthritis (ReA), systemic lupus erythematosus (SLE), juvenile idiopathic arthritis (JIA), - Chronic bacterial infections like mycobacterial and fungal arthritis, - Degenerative arthritis like osteoarthritis (OA), - Rare: most cases of neuropathic arthropathy (Charcot's joints), tumors, infiltrative diseases

Fig. 1.1  Approach to history taking in rheumatology

2-Duration - Acute: < 6 weeks - Chronic: > 6 week

1  History-Taking Skills in Rheumatology

5

onset of joints pains are septic arthritis and crystal-induced arthritis (after excluding trauma as a possible cause for joints pains) (Fig.  1.2). Gradual onset joint pains have long list of differential diagnoses including the classic rheumatological diseases like rheumatoid arthritis (RA) and SLE (see Fig. 1.2). 2. Duration: It is essential to determine whether the joint pains have been present for less or more than 6 weeks. Classically, arthritis caused by acute viral illnesses like parvovirus B19 infection can cause RA-like arthritis in distribution but with less than 6  weeks duration. Duration more than 6 weeks is an essential criteria to diagnose RA based on 2010 classification criteria of RA (see Chap. 25).

3. Patterns of joints affected: Each rheumatological disease has a pattern of presentation that should be recognized from this early stage. Each pattern has a differential diagnosis (Figs. 1.3 and 1.4). Predominant small joints involvement (like in pattern A) particularly the wrists, metacarpophalangeal (MCP), proximal interphalangeal (PIP), and metatarsophalangeal (MTP) joints is a classical presentation for RA. Other disorders like SLE, psoriatic arthritis (PsA), polyarticular gout, and reactive arthritis (ReA) can present in a similar way. The commonest joints involved in RA, for example, are wrists and MCP (2nd and 3rd). It has to be noted that distal interphalangeal (DIP) joints involvement is rarely ever involved in RA. These joints (DIP) are

Make sure the origin of the pain is from the joint itself, NOT from the periarticular sructures. One tip is to ask the patient to point the site of the pain by his/her finger!

Fig. 1.2  Identifying the site of the pain

Fig. 1.3  Patterns of joints affected

Differential Diagnosis

Joints

RA, SLE, PsA, Polyarticular gout and ReA.

Symmetrical polyarticular MCP PIP and MTP joints DIP joint(s) Bony swellings of DIPs or PIPs or CMC joint (base of thumb)

PsA, OA 1st

OA

Proximal girdle joints

Polymyalgia rheumatica and RA

Asymmetrical large joint oligoarticular disease

ReA, PsA, ankylosing spondylitis {AS)

Acute monoarticular disease

Infection, gout, pseudogout

Chronic monoarticular

PsA, RA, AS, OA and chronic infection (e.g. tuberculosis (TB))

Axial, sacroiliac and girdle joints

AS

Axial joints

Lumbar & cervical spondylosis/OA

Dactylitis (sausage digit)

PsA, ReA, AS, TB, sarcoidosis, sickle cell disease.

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L. Alharbi and H. Almoallim

a

RA

b

Reactive Arthritis

c

d

Psoriatic Arthritis

e

AS

Inflammatory OA of the hand

Fig. 1.4  Each rheumatological disease has a pattern. (a) Rheumatoid arthritis. (b) Reactive arthritis. (c) Ankylosing spondylitis. (d) Psoriatic arthritis. (e) Inflammatory osteoarthritis of the hand

1  History-Taking Skills in Rheumatology

7

predominantly involved in patients with PsA septic arthritis, while the first metatarsophaand inflammatory osteoarthritis (OA) of the langeal joints are the commonest joint hands. Classical presentation of inflammainvolved in gout. For chronic monoarticular tory OA of the hands (pattern E) involves joint involvement, a chronic infectious proDIPs, PIPs, and first carpometacarpal joint cess should be ruled out like tuberculosis or just at the base of the anatomical snuff. It has brucellosis. However, systemic rheumatic to be noted as a physical examination caveat diseases like RA can rarely present with a that the swellings of the joints in inflammamonoarticular joint only. tory OA of the hands are bony! It represents 4. Symmetry: This might have been covered the degenerative changes happening in the partly in the above section. It has been cartilage with osteophyte formation. included here to help the evaluator ­remember Predominant large joints involvement in the it all the time and consider it while composlower limbs (pattern B) is a classical presening the differential diagnosis. There are distation for ReA. A group of disorders called eases like PsA that can present in several spondyloarthritis (SpA) (include ankylosing different ways including symmetrical arthrispondylitis (AS), PsA, ReA, and arthritis tis like RA and asymmetrical arthritis involvassociated with inflammatory bowel diseases ing only few joints like the DIPs. Symmetrical (IBD-related arthritis) and undifferentiated arthritis does not include in the differential spondyloarthritis) (see Chap. 23 for detailed diagnosis only known rheumatological disclassification criteria) has particular predieases like RA and SLE. There are less comlection of large joints of the lower limb. mon diseases like sarcoidosis, and Sacroiliac joints can be involved in an asymparaneoplastic syndromes can present with metrical fashion (pattern B) in ReA or can be arthritis (Fig. 1.5). symmetrically involved (pattern C) with 5. Number of joints involvement (How many inflammation of all the insertions of tendons joints affected?): Again, this feature has been and ligaments to the bones of the back (this covered partially above (Figs.  1.6 and 1.7). is called enthesitis, and such inflammatory The emphasis is on a monoarticular single process in the back is called spondylitis). joint involvement when it should be considTherefore, (pattern C) is a classical presentaered a medical emergency. If a septic monotion for AS.  Spondylitis per say can be a articular joint was not diagnosed and treated manifestation of any disease of the SpA properly, it will lead unfortunately to irregroup of disorders. Large joints like proxiversible damage and lifelong disability if not mal girdle joints (shoulders and hips) can be death from disseminated infection [1]. It is involved predominantly in diseases like hard clinically to separate between oligoarpolymyalgia rheumatica and RA.  There is ticular and polyarticular in the initial workup one feature that is quite classical for PsA and as will be shown in Chap. 3. A list of possible crystal induced arthritis. It is the inflammadifferential diagnosis is provided for you just tion of all articular and periarticular structo give a knowledge background base to tures in one digit (dactylitis). This is not a ­proceed further in the history from patients feature for RA.  It has to be noted then, with joints pains. involvement of small joints like in (pattern 6. Associated symptoms: Obtaining history of D) with predominance of DIPs, dactylitis, redness, swelling, and morning stiffness is and asymmetrical sacroiliac joint involveessential in any patient with joints pains. Any ment is classical for PsA. severely inflamed joint will cause obvious For acute sudden monoarticular joint swelling observed by the patient. Keep in involvement, a septic process and/or crystal-­ mind that sometimes, swellings of the small induced arthritis should be ruled out. The joints can be detected by physical examinaknee joint is the commonest joint involved in tion only as the patient did not notice any

8

L. Alharbi and H. Almoallim Symmetry of the joints

Asymmetrical arthritis:

Symmetrical arthritis Inflammatory:

- RA, PsA, SLE, JIA (systemic and polyarticular types), adult onset Still’s disease, Sjögren’s syndrome - Other systemic rheumatic diseases: SLE, mixed connective tissue disease (MCTD), adult onset rheumatic fever, polymyalgia rheumatica, erosive inflammatory osteoarthritis, calcium pyrophosphate deposition disease (CPPD) (pseudo-RA type)

Infectious:

- Viral arthritis especially parvovirus arthritis - Lyme disease

Infiltrative:

- Sarcoid arthritis (acute type) - Amyloid arthropathy - Hemochromatosis arthropathy

Neoplastic:

- Primary infiltrative/paraneoplastic: Leukemia - Chemotherapy induced (classically post breast cancer therapy)

Endocrinal:

- Myxedematous arthropathy

lnflammatory:

- ReA - PsA - Pauciarticular JIA - Oligoaricular or polyarticular gout - CPPD disease (pseudogout type)

Infectious:

- Bacterial arthritis - Bacterial endocarditis.

Fig. 1.5  Symmetry of the joints Fig. 1.6  Number of joints involvement (How many joints affected)

MONOARTICULAR (Single joint)

OLIOONUICULAR (2-4 joints)

POLYARTICULAR (More than 4 joints)

DD

DD

DD

- Traumatic - Inflammatory: Pauciarticular JIA, crystal-induced - Infectious: bacterial, fungal, TB, viral (AIDS). - Neoplastic - Infiltrative: one type of chronic sarcoidosis - Miscellaneous: Acute coagulopathy, Hemoglobinopathy

- Oligoarticular JIA - Reactive Arthritis - Psoriatic arthropathy

- Inflammatory: RA, JIA (polyarticular and Still), adult Still, Sjögren’s - SLE and other connective tissue diseases - Seronegative spondyloarthropathies - CPPD disease - Vasculitides - Neoplastic: Paraneoplastic syndromes, metastasis, leukemia, lymphoma - Infiltrative: Sarcoidosis

1  History-Taking Skills in Rheumatology

9

Single red hot joint in RA: It should be remembered that the uncommon occurrence of a red hot joint in the context of RA may be due to superimposed septic arthritis and not to the disease process itself. Monoarthritis in SLE: The occurrence of monoarthritis in a patient with SLE suggests infection or osteonecrosis.

Fig. 1.7  Alarming presentation of arthritis in RA and SLE Fig. 1.8 Associated symptoms

Associated symptoms

Redness:

Swelling

Morning stiffness

DD: - Infections (gonococcal or non-gonococcal septic arthritis) - Crystal induced arthritis (gout, pseudogout) - Acute rheumatic fever - PsA - ReA

because of its small size. Redness is one of the cardinal signs of inflammation. Active RA does not cause redness usually unless there is a superimposed infection in that joint that it is red. Therefore red and swollen joints are caused classically by septic arthritis and/ or crystal induced arthritis (Fig. 1.8). 7. Constitutional symptoms: Obtaining these symptoms in any history obtained from patients for whatever symptoms presented is essential. Fever and arthritis are common clinical association. Again, septic arthritis whether in a monoarticular or polyarticular presentation should be ruled out. There is a full outline for this combination: fever and arthritis in Chap. 11. Apart from fever, the following symptoms should be obtained: weight loss, loss of appetite, night sweat, and fatigue. It has to be noted that patients with inflammatory arthritis often feel a general malaise. Fibromyalgia patients often report feeling ill (if I go shopping I am wiped out for the next 3 days). On the other hand, OA patients may be a bit tired but not really unwell.

8. Functional impairment: any inflamed joint will affect the functionality of the patient. The followings should be obtained: • How has the arthritis affected your daily ability to self-care? • How has the arthritis affected your ability to sleep well and to do things at home, work, and leisure? 9. Relieving and aggravating factors: Here the focus should be mainly on the effect of activity on the symptoms. Activity tends to aggravate joint pains caused by a degenerative process of the interarticular cartilage, i.e., OA, to be a reliving factor for inflammatory back pain as going to be shown in Chap. 6 about low-back pain. Use of nonsteroidal anti-inflammatory drugs (NSAIDs) tends to relive symptoms in a remarkable way in patients with inflammatory arthritis in comparison with patients with degenerative arthritis (OA) (Fig. 1.9). 10. Rheumatology review of systems: After your full analysis of the joints pain(s), now it is time to think which rheumatological diseases might be the top in your differential

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L. Alharbi and H. Almoallim Relieving and aggravating factors

Factors that relieve the symptoms: - Rset: OA. - Activity: classical relief in AS! - Medication (NSAIDs): symptoms are relived more in inflammatory conditions compared to degenerative conditions.

Factors aggravate the symptoms: - Activity: classical aggravate of OA! - Food e.g.: red meat: gout. - Medications: thiazide: gout.

Fig. 1.9  Relieving and aggravating factors

diagnosis. All rheumatological diseases are systemic diseases with significant involvements of other body parts (Fig. 1.10). Some patients may not correlate the relationship between numbness, tingling sensations, and joints pain(s) (some patients may present with arthritis and mononeuritis multiplex like in vasculitis or RA). Others may not remember to mention history of skin disease like psoriasis. Obtaining obstetric history is extremely important for any childbearing female patient as there are many complications in pregnancy related to SLE and/or APS (see Chap. 17). For all of these reasons, it is your rule to review all possible s­ ymptoms that might be present and help you in composing your differential diagnosis. All possible symptoms are complied in an approach from head to toe just to help you mastering this part of the history. • Past medical history: –– History of any rheumatic disease (RA, SLE, gout, psoriasis, etc.). –– History of recent infections (think of ReA!). –– History of chronic diseases. There are some rheumatological associations with diabetes mellitus (see Chap. 21). • Family history: –– Ask if similar condition happened in the family. –– Any family history of RA, SLE, psoriasis, etc.

• Medications and allergy: –– Detailed medication history. –– Any allergy from food and/or drugs? • Past surgical history: –– History of any previous operations. –– History of blood transfusion. • Social history: –– Marital status and occupation (tendinitis in typist!). How many children? Where do they live? –– History of contact with TB or jaundiced patients: essential prior to start of disease modifying anti-rheumatic drugs (DMARDs) and biological therapy.

1.3

Historical Correlation

Some patients may present initially with symptoms suspected for a certain disease. Then you need to check other symptoms related to this disease that might help you to make your diagnosis from historical grounds only! This is different than rheumatology review of systems mentioned above. Actually, as your skills in obtaining history from patients with joints pain grow, you will notice yourself combing this step with rheumatology review. For example, you are evaluating a young female patient with joint pains. You have a suspicion for SLE as you are proceeding in your history; then during your history taking, you should cover all common presentation of SLE!

1  History-Taking Skills in Rheumatology SYSTEMS

11 SYMPTOMS SHOULD BE ASKED

1- Hair

Hair loss, alopecia, psoriatic rashes (in the hair line)

2- CNS:

History of stroke, weakness, seizure, psychosis: SLE. Mononeuritis multiplex, peripheral neuropathy: vasculitis, SLE Lymph node enlargement in the neck: SLE, lymphoma with sjögren syndrome

3- Eyes:

Dryness: sjögren syndrome. Redness (uveitis): AS Pallor: anemia from many causes in RA or SLE.

4- Face:

Cheek: Photosensitivity: SLE Red cheeks (butterfly rash): SLE Scaring hyperpigmentation: SLE Parotid gland enlargement: sjögren Telangectasia: scleroderma Mouth: Dryness: sjögren syndrome Ulcer: SLE (painless), inflammatory bowel disease (IBD), Behcet’s, RA (from methotrexate use)

4- Chest (Respiratory & Cardiovascular systems):

SOB, chest pain, palpitation: SLE, RA History of PE/DVT: SLE, antiphospholipid antibody syndrome (APS) History of bronchial asthma: Eosinophilic granulomatosis with polyangitis (EGPA) (Churg- Straus)

5- Gastrointestinal tract (GIT):

Ask about all symptoms of GIT! History of jaundice: viral hepatitis. History of recent gastroenteritis or bloody diarrhea: ReA History of IBD: enteropathic arthritis. History of dysphagia: scleroderma History of HBV: vasculitis. History of HCV: chronic HCV can present as RA! Ask about risk factors of HBV, HCV and HIV prior to start any disease modifying antirheumatic drug (DMARDs).

6- Urinary system:

Frothy urine: lupus nephritis. Hematuria: lupus nephritis, anti-glomerular basement membrane disease (Goodpasture).

7- Sexual and obstetric history:

History of recent STD’s: ReA. History of oral/genital ulcers: Behcet’s disease. History of still birth at any age and/or history of three recurrent abortion: APS

8- Lower Limb:

History of non-palpable purpura, lower limb edema, nodules: vasculitis

9- Ask about Smoking and alcohol intake.

Smoking predisposes to RA, decrease response to DMARDs and biological therapy Adjust alcohol intake in patients recieveing methotrexate Alcohol is a risk factor for gout

Fig. 1.10  Rheumatological review of systems

The common symptoms for some diseases have been complied for you (Figure 1.11a, b, c historic correlation). Some of the questions may not be related to symptomatology! It might just address risk factors. If you are assessing a patient with

pain in the first MTP and/or with a red swollen knee joint and you are suspecting gout as a possible diagnosis, then you need to check for risk factors for gout: prior history of uric acid renal stones, alcohol intake and use of diuretics, etc.

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L. Alharbi and H. Almoallim Diseases

Certain historical points Ask about the following symptoms:

1- Patient with suspected SLE

- Alopecia (hair loss) - Malar rash - Mouth ulcer - Photosensitivity - Discoid lupus - Raynauds phenomenon - Pleuritic chest pain - Headache - Hematuria - Psychosis, seizures - Vascuilitic rash - Urinary symptoms - Detailed obstetric history Ask about the following symptoms:

2- Patient with suspected vasculitis

3- Patient with suspected myositis

4- Patient with suspected gout

- Claudication: Takayasu’s arteritis - Fatigue, fever, myalgias, headache, diplopia, jaw claudication: giant cell arteritis - Wight loss, myalgias, peripheral neuropathy (numbness), abdominal pain, livedo retieularis: Polyarteritis nodosa (PAN) - Sinusitis, saddle nose deformity, hemoptysis, chest pain, hematuria, uveitis, history of DVT or PE, granulomatosis with polyangiitis (GPA) (Wegener’s) or microscopic polyangiitis (MPA). - History of Asthma, granulomatous vasculitis, eosinophilia: EGPA. - Abdominal pain, palpable purpura, polyarthralgias, microscopic hematuria: IgA vasculitis (IgA V) (HenochSchonlein). - Oral/genital ulcer, uveitis, erythema nodosum: Behcet’s syndrome. - Weakness: gradual, progressive, painless, symmetrical and proximal. It may involve shoulder, pelvic girdle and neck flexors, but no involvement of facial or ocular muscles! - Dermatologic: erythematous rash on sun exposed skin, heliotrope rash over upper eyelid, Gottron’s papules over the dorsum of PIP and MCP joints. Ask about: - Myalgia and arthralgia. - Dysphagia and dysphonia. - Raynoud's phenomena. - Symptoms suspected of malignant conditions: weight loss, fatigue, bleeding per rectum, smoking and chronic cough .. etc. - Drugs. - Pain in 1st MTP (sudden onset), may involve ankles, feet and knees, bursitis (olecranon, patellar). - History of previous attack of gout, chronic tophaciuos gout (deforming arthritis). - Risk factors: uric acid renal stones, history of hyperuricemia, chronic renal disease, myelo & lymphoproliferative diseases, increase meat, seafood and alcohol intake, use of diuretics and pyrazinamide. - Alcohol. - Family history of gout. Ocular: dry eyes Mouth: dry mouth, decrease salivation, drinking fluid while swallowing, difficulties with speech, change in taste and parotid enlargement Ask about the following risk factors:

5- Patient with suspected Sjögren’s syndrome

- Head and neck radiation. - AIDS. - HCV. - Lymphoma. - Sarcoidosis. - Anticholenergic drugs. - GVHD (graft versus host disease) Ask about the following symptoms:

6- Patient with suspected Spondyloarthritis

- Red eye (uveitis) - Psoriasis - Recurrent/previous infections: gastroenteritis, STDs, tonsillitis - Dysphagia - IBD - Inflammatory back pain - Lower limb joints pain - Plantar fasciitis/Achilles tendinitis Ask about the following symptoms:

7- Patient with suspected Septic Arthritis.

- Joint pain, - Joint swelling or history of joint edema, - Fever, - Sweating and Rigors (I) - Role out any source of local or disseminated infections by asking about: - Headache - Sore throat - Productive cough - Urinary symptoms, GI symptoms. - History of wound infection or abscess.

Fig. 1.11  Historical correlation

1  History-Taking Skills in Rheumatology

1.4

Physical Examination

This is just to remind you about the particular approach of physical exam techniques that should be performed and then presented (Fig.  1.12). A comprehensive approach to joints examination is presented in Chap. 2.

1.5

How to Present your Case

You are ready now to present your case! You have built an organized approach to history taking from patients with joints pain(s). You have performed a comprehensive physical examination focusing on evaluation of these joints and whether there is true articular process like arthritis or periarticular process like tendinitis (see Chap. 22). Simply you need to present your history and physical examination in the same manner mentioned above with focusing on positive findings and important negatives. After your history and physical examination presentation, it is required from you to sum up all your information together. It is better to start with your impression (summary of the case) and then your problem list and differential diagnosis. Fig. 1.12 Physical examination

13

1.5.1 Impression This (age) who is (known to have (chronic diseases)) presents with: • History (usually presenting complain). • Physical exam(mention obvious findings). • Lab results (mention the important results related to the case) (if it is known to you).

1.5.2 Problem List In this section you have to make a list with all your patient’s problems or complains starting with the most serious and important one. This should guide you to reach the diagnosis easily. This is a suggested approach on how to write a problem list: Regarding the first problem: 1. Write your differential diagnosis for this issue and mention which diagnosis is more relevant with your case and why. 2. Write your management plan, if further investigations and/or referral are needed.

Physical Examination

Details

1- General Appearance and Vitals sign

As usual.

2- General Exam

Eyes Scalp Mouth Parotid Neck lymph nodes Skin (redness, thickness) Nails (pitting, periangular erythema)

3- Specific exam for any joint

I- General appearance: Deformity , swelling II- Inspection: Skin: redness, sacrs and rash Ligaments and tendons Muscles Bones Ill- Screening Exam: Check for range of motion (ROM) IV- Palpation: Effusion, tenderness, warm and crepitus. V- Range of motion: Active and passive. VI- Special tests.

4- Examination of the other systems

CNS, CVS, Chest and Abdominal exam.

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L. Alharbi and H. Almoallim

See the diagram below for more details (Fig. 1.13).

of their chronic disease. Here are suggested tips for you to help you deal with these patients. You should ask about:

1.6

1 . Pain (how he/she is doing since last visit). 2. Which joints are particularly affecting you today? 3. Associated symptoms (morning stiffens (mins), swelling). 4. How well controlled do you feel the arthritis is? 5. What drugs are you taking? Your adherence? Do you get any benefit? 6. Any functional impairment? You should not forget to: 7. Do not forget to examine his/her all joints. 8. Do not forget to review all his/her medications. 9. Do not forget to review his/her previous investigations (Fig. 1.14).

Follow-Up Patient

Established patients with rheumatological diseases have frequent visits to outpatient clinics. They come for routine visits for assessing the progress of their disease and review the management plan

Problem Lists

X1

X2

X3

X4

DD: 1 → because of ........ However this is not typically a feature of ... 2 → because of ......

1.7

Plan: 1-further investigations: Labs, imaging, ivasive (biobsy)

1.7.1 Boolean-Based Definition [2]

 he 2011 ACR/EULAR T Definitions of Remission in Rheumatoid Arthritis Clinical Trials

At any time point, patient must satisfy all of the following: Plan: 2-Non-pharmacological measures: Physiotherapy, occupational therapy, diet excercise, counselling

Plan: 3-Pharmacological measure: 1-Drug: why? Explain side effects, monitoring, baseline screening, prophylaxis

• • • •

Tender joint count ≤1+ Swollen joint count ≤1+ C-reactive protein ≤1 mg/dl Patient global assessment ≤1 (on a 0-10 scale)+.

1.7.2 Index-Based Definition Simplified Disease Activity Index score of ≤3 [3]. Definitions for some of the outcome measures in rheumatology are compiled in Fig. 1.15. Further

Plan: 4-Other referral.

Fig. 1.13  Problem lists Fig. 1.14 Outcome measures of the disease activity

Outcome measures of the diseae activity:

DAS28

CDAI

SDAI

1  History-Taking Skills in Rheumatology Outcome measures of the disease activity

15

Parameters

Interpretation

1-DAS28

a. How many Tender joints? b. How many Swollen joints? c. ESR or CRP level.

1- DAS28 2.6 and 3.2 and 5.1: High Disease Activity

2-CDAI

a. How many Tender joints? b. How many Swollen joints? c. The PGA represents the patient’s self-assessment of disease activity (0 to 10 scale) d. The EGA represents the evaluator's assessment of disease activity(0 to 10 scale)

1- CDAI 2.8 and 10 and 22: High Disease Activity

3-SDAI

a. Tender joint count (using 28 joints) b. Swollen joint count (using 28 joints) c. PGA (0 to 10 scale) d. The EGA (0 to 10 scale) e. CRP level

1- SDAl 3.3 and 11 and 26: High Disease Activity

Fig. 1.15  Outcome measures of disease activity in RA and their interpretation

reading is required from you to know more about the implications of its use in the management of patients with RA (Fig. 1.15 outcome measures of disease activity in RA and their interpretations).

Abbreviations AIDS

Acquired immunodeficiency syndrome AS Ankylosing spondylitis CDAI Clinical Disease Activity Index CMC Carpometacarpal joints CNS Central nervous system CPPD disease Calcium pyrophosphate dihydrate disease CVS Cardiovascular system DAS-28 Disease activity score DIP Distal interphalangeal DVT Deep venous thrombosis EGA Evaluator Global disease Activity

GVHD HBV HCV IBD JIA MCP MCTD

Graft vs. host disease Hepatitis B virus Hepatitis C virus Inflammatory bowel disease Juvenile idiopathic arthritis Metacarpophalangeal joints Mixed connective tissue disease MTP Metatarsophalangeal NSAIDs Nonsteroidal anti-inflammatory drugs OA Osteoarthritis PAN Polyarteritis nodosa PE Pulmonary embolism PGA Patient Global disease Activity PIP Proximal interphalangeal RA Rheumatoid arthritis SDAI Simplified Disease Activity Index SLE Systemic lupus erythematosus STDs Sexually transmitted diseases

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References 1. Margaretten ME, Kohlwes J, Moore D, et  al. Does this adult patient have septic arthritis? JAMA. 2007;297:1478–88. 2. Balsa A, Carmona L, González-Alvaro I, et al. Value of disease activity score 28 (DAS28) and DAS28-3

L. Alharbi and H. Almoallim compared to American College of Rheumatologydefined remission in rheumatoid arthritis. J Rheumatol. 2004;31(1):40–6. 3. Aletaha D, Smolen J. The simplified disease activity index and clinical disease activity index to monitor patients in standard clinical care. Rheum Dis Clin N Am. 2009;35:759–72.

Open Access  This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made. The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

2

Approach to Musculoskeletal Examination Hani Almoallim, Doaa Kalantan, Laila Alharbi, and Khaled Albazli

2.1

Introduction

Musculoskeletal (MSK) symptoms are one of the most common reasons for patients to seek medical attention. Despite the high prevalence of musculoskeletal disorders in all fields of clinical practice, doctors continue to describe poor confidence in their musculoskeletal clinical skills. Here in this chapter an overview of the epidemiology of MSK disorders and the current status of MSK competency skills among clinicians will be discussed. Then a general approach to MSK examination will be introduced. The rest of the chapter will address detailed approach to upper H. Almoallim (*) Professor of Medicine, College of Medicine, Umm Al-Qura University (UQU), Makkah, Saudi Arabia e-mail: [email protected] D. Kalantan Al-Noor Specialist Hospital, Makkah, Saudi Arabia L. Alharbi College of Medicine, Umm Al Qura University, Makkah, Saudi Arabia College of Medicine, Skåne University Hospital, Malmoe, Sweden K. Albazli Department of Medicine, Faculty of Medicine in Al- Qunfudhah, AlUmm Al-Qura University, Makkah, Saudi Arabia The George Washington University School of Medicine and Health Sciences, Washington, D.C., USA © The Author(s) 2021 H. Almoallim, M. Cheikh (eds.), Skills in Rheumatology, https://doi.org/10.1007/978-981-15-8323-0_2

limb and lower and back joints examination. Each section will start with a brief approach to pains originating from each site. Good history is part of the MSK examination.

2.1.1 Objectives 1. To discuss the current status of musculoskeletal (MSK) examination competency skills among clinicians. 2. To construct a diagnostic approach to single joint pain. 3. To demonstrate a comprehensive approach to MSK examination of all body joints.

2.2

Epidemiology of Rheumatic Diseases

MSK symptoms are the most common health complications requiring medical attention and accounting to 20% of both primary care and emergency room visits. MSK conditions affect one in five adults [1]. In a health survey, MSK disorders were ranked first in prevalence as the cause of chronic health problems, long-term disabilities, and consultations with a health professional [2]. In Saudi Arabia, MSK disorders are the second major cause of outpatients visit in primary care centers and private clinics. This is corresponding to findings in several other reports from different parts of the 17

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H. Almoallim et al.

world. Low back pain is the most prevalent of musculoskeletal ­conditions; it affects nearly everyone at some point in time and about 4–33% of the population at any given point [2]. MSK disorders are a very common cause of health problems. They result in limiting work in developed countries. Besides, up to 60% of people on early retirement or long-term sick leave claim a MSK problem as the reason [1].

2.3

 urrent Status of MSK C Examination

A continuous neglect is observed in musculoskeletal examination skills in clinical practice.

Thus problems of patients with complaints about bones and joints are often ignored and underestimated by doctors. Many studies suggest that training in MSK disorders is inadequate in both medical schools and most residency training programs. In Saudi Arabia and in many parts of the world, undergraduate and postgraduate medical teaching of MSK disorders is currently brief and not directly relevant to the knowledge and skills commonly required for management of these conditions in an outpatient setting [1, 3]. Educational deficiencies in MSK disorders have been reported extensively in undergraduate curricula and postgraduate training programs (Box 2.1) [3].

Box 2.1 Educational deficiencies in MSK examination skills Causes of musculoskeletal (MSK) examination skills deficiencies [2]   1. Vague training of MSK disorders in undergraduate programs.   2. Examination of the MSK system is often regarded to be complex in comparison with other organ systems.   3. Underestimation of the prevalence of MSK conditions and their impact on individuals and society.   4. MSK disorders are not considered to be main competencies of medical graduates because they are not life threatening conditions.   5. The lack of standardized approach to the clinical assessment of MSK problems, whether pertaining to primary care, rheumatology, or orthopedics.   6. Lack of proper standard teaching in MSK disorders results in the low competence in MSK examination skills.   7. Lack of summative evaluation of MSK examination skills contributes to low level of competency among medical graduates.   8. The disparity in the approach to examination between rheumatologists and orthopaedic surgeons mostly lead to poor performances in MSK examinations.   9. The lack of appropriate teaching and evaluation in MSK disorders; clinical teachers are not usually skilled in MSK examinations and thus bone and joint diseases are not screened.

Solution of MSK examination deficiency [2] 1. To define competencies that should be mastered while dealing with MSK disorders. 2. To agree on what MSK skills should be mastered by medical students. 3. Standardized approach to the clinical assessment of MSK problems (Figs. 2.1 and 2.2). 4. Experts in various specialities work more closely together and look for the commonality of approach when treating a patient as they often treat the same patients but from separate angles. 5. Another solution would be an integrated MSK disease course for medical students, bringing together orthopedics, rheumatology, and physical medicine and rehabilitation. This approach has been found to be effective. 6. The method of teaching MSK examination skills should follow interactive approaches and hands-on teaching sessions where learners are involved in the teaching process.

2  Approach to Musculoskeletal Examination

As there is no standardized approach to the clinical assessment of MSK problems, one of the direct solutions for this is to have unified approach to MSK disorders. The approach should consist of screening examination (this is basically active range of motion testing (ROM)), inspection, palpation, ROM, and special tests (see below). The other direct solution is to have a clear objective from each MSK examination encounter based on historical facts obtained from patients. Each clinician should have then an objective for the MSK examination, whether signs of arthritis to be sought or signs of periarthritis with soft tissue inflammation (ligaments, tendons, bursae, cartilage, etc.). For example, a young female patient with small joints pain for 6 weeks should have a different objective for the MSK examination than a young male with knee joint pain following a football match. The objective for the MSK examination for the female patient with small joints pain should be to look for signs of arthritis, while the objective for the MSK examination of the male patient is to look for signs of periarthritis mainly ligamentous or meniscus injuries in his knee. This is not to underestimate the comprehensive approach to any joint with performing all steps (screening, inspection, palpation, ROM, special tests) but rather to get more focus on the techniques that should yield the signs suggestive of the preliminary diagnosis that was made initially based on the history obtained from the patient. A number of different medical specialties are usually involved in treating patients with musculoskeletal complaints. This comprises general practitioners, family physicians, internists, orthopedic, and surgeons. However, the various practitioners may work in teams with other health professionals, but they often lack a multispecialty focus which results in treating the same patients in a segmented manner and from different inconsistent angles. Based on a literature review published with details in reference [2], Box 2.1 shows some summarized causes of MSK examination skills deficiencies. Some suggested solutions were mentioned as well. One of these solutions is to have a standardized approach to MSK examina-

19

tion (see examination of the hand and wrist joints) (see Table 2.1.)

2.4

 eneral Approach to MSK G Examination

Clinicians have perceived the MSK examination across the world as complex and difficult to perform. This can be solved if the approach to MSK examination across different disciplines were unified. This approach starts by initiating the MSK examination using the following steps: • Inspection: The basic anatomical structures overlying joints should be inspected for any changes. This includes inspection of the skin, tendons, muscles, and bones (joints). Skin changes like redness, rashes, and color changes should be noted. Loss of skin wrinkling may indicate swelling in underneath structures. Synovial sheaths covering tendons might be swollen. Muscles might be wasted. Bone and/or deformities might be obvious to observe. • Screening exam: this is basically an active range of motion (ROM) testing to assess for gross pathology. The patient performs the full range of movement of the examined joint by own effort. If the active ROM was entirely normal without any limitation and/or pain, the joint examined can be considered normal. This step is introduced early on in this approach in order to focus the detailed MSK exam in joints with significant abnormal active ROM testing. The screening exam might be normal for arthritis affecting small joints of the hand and/or feet particularly in early stages of arthritis. • Palpation: this is basically palpating for tenderness over different anatomical structures (bone, joint, tendons, bursae, fascia). Tenderness over the joint line (where two bones forming the joint are meeting) might indicate arthritis. There are special approaches to palpate small and large joints that will be explained in this chapter. Palpation for one of

20

the cardinal signs of inflammation, hotness (warmth), should be considered as well. • Range of motion testing: there is active and passive ROM testing. If you have done the active ROM during the screening exam, you may now just perform the passive form or repeat it again. In cases of true intra-articular disease process (true inflammation of synovial membrane as in case of inflammatory arthritic disorders, for example, rheumatoid arthritis or psoriatic arthritis), the active and the passive ROM will be both restricted. While in cases of periarticular disease processes (affecting tendons, ligaments, bursae, fascia) the active ROM will be restricted and/ or limited with tenderness, the passive ROM should be entirely normal. It is normal because you exclude the contribution of the affected tendon or ligament in the movement by doing it passively. However, there are exceptions to this general rule. Handling of the joints during MSK examination is essential. You should avoid assessing ROM while you are holding the joint itself. You should hold the assessed joint from distal and proximal areas trying also to hold other joints. You should mainly assess the ROM by holding bony structures forming the joint rather than the joint itself. This is not to cause pain over the joints from your holding. An issue might interfere with your ability to evaluate the origin of the pain; whether from the ROM or from your holding that causes stress over the joint results in pain. • Special tests: these tests are conducted to examine for possible causes of the joint pain particularly soft tissue structures around the joint. As a general rule to examine for tendonand/or ligament-related problems, you need to “stretch” the tendon to assess if this stretch can aggravate the symptoms and/or to “stress” it. If the function of tendon that you are assessing is extension, for example, to stress it you need to exert your force as an examiner in flexion while the patient is maintaining his joint in extension and resisting your flexion. If there is tenderness while performing this test, it might be due to tendinitis.

H. Almoallim et al.

• Complete your exam: the MSK exam for any particular joint is not complete without evaluating other joints (above and below the joint being examined). In addition, a neurovascular evaluation is essential to exclude any possibility of neurological and/or vascular origins of the joint pain. Assessing peripheral pulses, examining the motor system, and evaluating for sensory loss are essential for comprehensive evaluation. There are two important steps that should be addressed for any patient with joints pain. The first is determining in your history the location of the pain whether it is anterior, posterior, lateral, or medial pain. This could be achieved by simply asking the patient to point by his/her finger to the site that is causing pain at the joint. Each one of these sites has its differential diagnosis as a cause for pain. This should lead to the next step that is considering the anatomical structures at the site of the pain determined by the patient. You should continue taking your comprehensive history addressing the risk factors and trying to rule in or rule out the possible differential diagnosis you created by now from these steps. After completing your history, you should determine now the objective of your MSK examination. Examining a young female who presents with small joints pains should have different objective than examining a young college student who presents with knee joint pain after a soccer game! For the young female patient, your objective should be looking for signs of arthritis: small joints pain swelling and/or tenderness. You may base on your history to look for signs of systemic lupus erythematosus, for example. While the objective of MSK examination for the college student should be to look primarily for signs of soft tissue injuries in his affected knee. This is not to underestimate the value of performing comprehensive MSK examination for the affected joint. It is rather a process to construct an approach to diagnosis utilizing historical findings and combining it with an objective-oriented MSK examination. The following section is divided into three: the upper limb, the lower limb, and the back examination. Each section starts with a brief review of

2  Approach to Musculoskeletal Examination

21

the anatomy and then a description on the approach to pain origination from that particular joint. This is followed by a stepwise approach to examination of that joint using the inspection, screening exam, palpation, ROM, and special tests approach. The reader should realize the importance of applying the knowledge learned from this chapter into practice. This continued practice is the assuring way to the mastery level in competency skills in MSK examination.

2.5

Musculoskeletal Examination of Upper Limb Joints (Fig. 2.1)

The joints included in upper limb are hand and wrist, elbow, and shoulder. There is a brief review of the important anatomical landmarks that should be mastered because it has clinical correlations. This will be referred to as the first step. Then an approach to pain originating from this joint will be discussed focusing on anatomical

differential diagnosis. The second step will be to follow the stated approach in MSK examination with descriptions whenever it is necessary. Illustrations have been used sometimes as a self-­ explanatory toll.

2.5.1 The Hand and Wrist Joints 2.5.1.1 First Step: The Anatomy  natomy of the Hand Joints (Fig. 2.1) A Each hand consists of 27 bones: 8 carpals, 5 metacarpals, and each finger having three phalanges except the thumb which has only two phalanges (Fig. 2.1). The joint is the articulation between two bones, so between the two phalanges there is interphalangeal joints, proximal (PIP) and distal (DIP); between the phalanges and m ­ etacarpal bones, metacarpophalangeal joint (MCP); between the metacarpals and carpal bones, carpometacarpal joint (CMC); and between the carpals bones, the intercarpal joints.

Fig. 2.1  Anatomy of the hand Middle Phalanges

Sesamoid Bone

DIP

PIP

Distal Phalanges

MCP Poximal Phalanges

Metacarpal Bone Hamate Trapezium Pisiform Trapezoid Triquetrum Capitate Scaphoid

Lunate

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There are around 62 muscles in the hand divided as intrinsic and extrinsic muscles. The intrinsic muscles are thenar, hypothenar, and interosseous muscles. The extrinsic muscles are flexors in the volar of the hand and extensors in the dorsum of the hand. There is also the synovial sheath, which is always involved in inflammatory arthritis. The hand is innervated by three important nerves, which are radial nerve providing sensory supply to the dorsum of the hand, median nerve providing sensory supplies to three, and half finger and ulnar nerve sensory supplying the little finger and half of ring finger. All the small muscles of the hands are supplied by ulnar nerve except (LOAF) the lateral two lumbricals, opponens pollicis, the abductor pollicis brevis, and the flexor pollicis brevis. Be aware that the extensors of the thumb are supplied by radial nerve.  pproach to Hand Pain A The approach of any patient presenting with hand pain should include: • History. • Physical examination. • Differential diagnosis. In the history, you should ask about the location of the pain whether it is located in the dorsal, volar, radial, or ulnar sides of the hand (Table 2.1). Then you should think about the anatomical structures in each one of these sites and what possible diseases might cause the pain. If the patient presents with dorsal pains, the anatomical structures that might be included are MCPs, PIPs, DIP joints, or wrist joint. The ­diseases that affect these joints are mainly arthritic disor-

ders. Detailed approach to history taking should be undertaken as it was explained in Chap. 1. Tendons can be involved which result in tendinitis or, if the entire finger is swollen, dactylitis. The anatomical structures included in patients presenting with volar pains are flexor tendons causing flexor tenosynovitis or what is known as trigger finger. Palmar fascia involvement results in Dupuytren’s contracture. Median nerve compression as it passes below the flexor retinaculum causes a condition called carpal tunnel syndrome. If the patient presents with radial pain (the thumb), the anatomical structure are snuffbox area. This is surrounded laterally by tendons of extensor pollicis brevis and abductor pollicis longus muscles, medially by tendon of extensor pollicis longus muscle and in the roof the scaphoid bone. The classical diseases affecting this area are de Quervain’s tenosynovitis and first carpometacarpal osteoarthritis. Other diseases like thumb fracture and extensor carpi radials tendinitis are less commonly observed. Ulnar pain is rare. Possible diseases affecting this site of the hand could be originated from ulnar nerve compression, tenosynovitis of flexor carpi ulnaris, and/or traumatic injuries.

2.5.1.2 Second Step: The Approach It is always: • Inspection. • Screening exam. • Palpation. • Range of motion. • Special tests.

Table 2.1  The differential diagnosis of wrist and hand pain according to the location of the pain Dorsal Arthritis   •  Wrist   •  MCP   •  PIP   •  DIP   •  Tendinitis     –  Dactylitis Trauma:   –  Scaphoid fracture

Volar •  Carpal tunnel syndrome •  Dupuytren’s disease •  Trigger finger •  Arthritis

Ulnar •  Trauma •  Ulnar nerve entrapment •  Tenosynovitis: Flexor carpi ulnaris

Radial •  Anatomical snuff box: –  De Quervain’s tenosynovitis –  First carpometacarpal osteoarthritis •  Tenosynovitis of extensor carpi radialis •  Trauma: Thumb fracture

2  Approach to Musculoskeletal Examination

23

Inspection Nails: evidence of psoriasis, vasculitis. Skin: redness, scars, rashes. Muscles: wasting, atrophy. Bones and joints: swelling, deformities. Remember: • Always inspect dorsal and palmar aspects. • Start distally to proximally.

Screening Exam The aim is to screen for gross pathology. • It is basically active ROM testing. • First, extend fingers and wrist (palmar aspect upward). Make a fist, and then extend again. Make a tuck position, and then extend again. Make a prayer sign and then wrist flexion with all fingers facing the ground opposite of the prayer sign. Lastly, assess grip strength (Fig. 2.2). Palpation The major aim is to look for evidence of arthritis in the form of warmth, effusion, and joint line tenderness. Palpate: joints, bone, and soft tissue. Start with dorsum of the hand for nodules; palpate MCPs with a scissor technique and PIPs Fig. 2.2 (a) Wrist flexion and (b) wrist extension

and DIPs with four fingers technique, follow the third metacarpal bone to feel capitate and the joint line of the wrist; and then feel scaphoid in the anatomical snuff box and other bones for tenderness. Make a scissor-like shape with your fingers, joining the index and middle fingers together and joining the ring and little finger together. Hold the patients hand from the sides at MCPs level. Flex the MCPs to 90° and with your two free thumbs from both hands, feel the joint line for every MCP joint to assess for effusion, swelling, and/or tenderness (Fig. 2.3) [3]. This technique is called four fingers because you should use your four fingers which are the thumb and index finger of each hand (Fig. 2.4). With your thumb and index fingers of one hand, hold each PIP from the side and press firmly. With your other hand’s thumb and index fingers, hold the same PIP joint from an anteroposterior direction and push intermittently in and out, looking for effusion, swelling, and/or tenderness [3]. With your thumb, follow the third metacarpal bone on the dorsal aspect of the hand until reaching a dimple at the capitate level (Fig. 2.5). Your thumb should exert a firm, continuous pressure on this point with your other thumb pushing intermittently in and out, just half an inch away from the other thumb on the wrist joint line, looking for effusion, swelling, and/or tenderness [3].

a

b Phalen’s test

Prayer sign

Wrist Flexion

Wrist extension

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H. Almoallim et al.

Fig. 2.3  Scissor technique

Fig. 2.4  Four fingers technique

Range of motion • You have done active ROM in your screening exam. • Do it again for the wrist joint: extension, flexion, ulnar deviation, and radial deviation. • For passive ROM of the wrist: hold the distal forearm with one hand, and grasp the palmar aspect with the other hand. Avoid holding the hand from the MCP site as this might be painful if there is arthritis. • Now move the wrist passively to extension, flexion, ulnar deviation, and radial deviation. You should observe and comment on tenderness, stiffness, and/or limitation of movement and end-range stiffness. All these are expected signs of arthritis.

Fig. 2.5  Two thumbs technique

Special tests • This is to assess stability of the wrist joint. This is important particularly in pain in wrist joint following traumatic injuries. • For de Quervain’s tenosynovitis: do Finkelstein’s test (Fig.  2.6). This is simply a trial to overstretch the tendon and examine for tenderness if it is elicited with this technique to suggest the diagnosis. To stress the tendon, push the extended thumb to flexion and ask the patient to resist your flexion. If there is pain, this would confirm the diagnosis. • Carpal tunnel syndrome is reviewed thoroughly in “Diabetes and Rheumatology” Chap. 21.

2  Approach to Musculoskeletal Examination

25

Fig. 2.6 Finkelstein’s test

Extensor Pollicis Brevis Abductor Pllicis Longus

Finkelsten’s test

2.5.2 The Elbow Joint 2.5.2.1 First Step: The Anatomy (Figs. 2.7 and 2.8) The elbow joint is composed of three bones, which articulate together to form three joints, three ligaments, and muscles. The bones that form the joints are the distal part of the humerus, the proximal part of the radius, and the ulna laterally and medially. They articulate together to form three joints, the humeroulnar joint, the radiohumeral joint, and the proximal radioulnar joint. These joints are held together through a network of ligaments; the major three ligaments are the medial collateral ligament, the lateral collateral ligament, and the annular ligament. What makes the elbow flex, extend, supinate, and pronate are the muscles of the elbow joint, such as the biceps muscles and its tendon, the triceps muscles, the brachioradialis, the flexor forearm muscles attached to medial epicondyle, and the extensor forearm muscles attached to

lateral epicondyle. Branches from median, ulnar, musculocutaneous, and radial nerves supply this joint.  pproach to Elbow Pain A The approach to any patient presents with elbow pain should include: • History. • Physical examination. • Differential diagnosis. In the history you should determine the location of the pain by simply asking the patient to point to the tender spot in his elbow. Lateral elbow pain is the most common site for clinical presentation. Other sites are medical and posterior elbow pains. After determining the site, then a simple standard approach should be followed including the onset of the pain, its duration, severity, radiation, aggravating and reliving factors, and history of trauma. The occupation of the patient as well as detailed history of sports activities is essential to obtain.

26 Fig. 2.7  Elbow Joint anatomy: bones

H. Almoallim et al.

a Humerus Lateral supracondylar ridge

Medial supracondylar ridge

Radial fossa

Coronoid fossa

Lateral epicondyle

Medial epicondyle

Capitellum

Trochlea

b Trochlear notch Coronold process

Head and neck of radius

Radial notch Ulna

Radial tuberosity Radius

Fig. 2.8  Elbow Joint anatomy: nerves and ligaments

a Humerus

Ulnar nerve

Medial epicondyle Annular ligament Oblique cord

Ulnar coliateral ligment

Radius

Ulna

b Humerus Head of radius Lateral epicondyle Radius Radial collateral ligament

Ulna

Olecranon bursae Annular ligment

2  Approach to Musculoskeletal Examination

Box 2.2 Differential Diagnosis of Elbow Pain Lateral elbow pain Common:   1. Lateral epicondylitis   2. Referred pain (cervical, upper thoracic spine) Less common:   1. Synovitis   2. Radiohumeral bursitis   3. Radial tunnel syndrome (posterior interosseous nerve entrapment) Not to be missed:   1. Osteochondritis dissecans. Medial elbow pain Common:   1. Medial epicondylitis   2. Medial collateral ligament sprain Less common:   1. Ulnar neuritis   2. In children: Avulsion fracture of the medial epicondyle Not to be missed:   1. Referred pain Posterior elbow pain   1. Olecranon bursitis   2. Triceps tendinopathy   3. Posterior impingement

Repetitive minor trauma from overuse might precipitate epicondylitis with micro tears affecting the common tendon insertion. You may ask also about functional limitation, swelling, and/or instability of the joint. A swollen elbow should lose its ability to be fully extended. History of shoulder and/or neck pain should be obtained as pain in the elbow may be simply a referred one from these sites. Differential Diagnosis Depends on the location of pain (Box 2.2).

2.5.2.2 Second Step: The Approach It is always: • Inspection. • Screening exam. • Palpation. • Range of motion. • Special tests.

27

Inspection Examine both elbows for asymmetry Expose the upper arm completely and examine: • Skin: rashes, abrasions, erythema, redness, scars, subcutaneous nodule, subcutaneous psoriasis. • Muscle: wasting, atrophy. • Bones and joints: –– Swelling: localize over olecranon bursae, e.g., olecranon bursitis or diffuse particularly in area between olecranon process and lateral or medial epicondyle, e.g., elbow arthritis. –– Deformity: assess the carrying angle (Fig. 2.9): Ask patient to extend arm in anatomical position (palm facing anteriorly), the longitudinal axes of upper arm and forearm from a lateral (valgus) angle at elbow joint known as the carrying angle (5°in male, 10°–15° in female). Screening Exam • The aim is to screen for gross pathology. • It is basically active ROM testing (Fig. 2.10). • A quick way to evaluate this is to ask patient to comb the hair and watch any abnormal moment. • Ask patient to do: –– Extension. –– Flexion. –– Supination. –– Pronation. Palpation Should include palpation of: • Skin and soft tissue: muscles, ligaments, tendons, and epitrochlear lymph nodes. This lymph node is located just 1 cm above medical epicondyle in the antecubital fossa and then 1 cm distally on the shaft of the ulna. It is hard to feel in obese patients. • Bony landmarks that should be palpated: –– Medial epicondyle: any tenderness suggestive of medical epicondylitis. –– Medial epicondylar ridge: any tenderness suggestive of elbow joint arthritis?

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Fig. 2.9  Abnormality in carrying angle: (b, d) Cubitus valgus. (a, c) Cubitus varus (gunstock deformity). Effect of swelling: it holds the joint in partial flexion [4]

a

b

c

d

–– Lateral epicondyle: any tenderness suggestive of lateral epicondylitis? –– Lateral epicondylar ridge: any tenderness. –– Olecranon process: any tenderness suggestive of olecranon bursitis? –– Superficial surface of the ulna (as far distal as the wrist). –– Radial head. • Elbow joint line: palpate for tenderness, effusion, and/or nodules. Ulnar nerve: runs in capital groove behind the medial epicondyle.

Start by palpating the posterior aspect: the three palpation landmarks (the medial epicondyle, the lateral epicondyle, and the apex of the olecranon) form an equilateral triangle when the elbow is flexed 90° and a straight line when the elbow is in extension. The points between the olecranon process while the elbow is in 90° of flexion and the medical or lateral epicondyle represent the joint line of the elbow joint (Fig. 2.11). If there is tenderness elicited while palpating these points, it indicates elbow joint arthritis. Otherwise, effusion may be elicited by palpation.

2  Approach to Musculoskeletal Examination Fig. 2.10  Active range of motion of the elbow joint

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a

b

Flexion

Extension

Supination

Range of Motion • You have done active ROM in your screening exam. • Place one of your examining hands just above the elbow joint holding the distal end of the arm. The other hand should be holding the distal end of the forearm just few centimeters above the wrist joint. Examine passive range of motion for the following actions: –– Flexion: bend the patient’s elbow slowly by bringing both of your hands together. –– Extension: move your hands away from each other to extend the patients elbow. Note that some patients particularly females may have hyperextensible joints that may cause few extra-degrees of elbow hyperextension. –– Supination: with the hand holding the distal forearm, bring the palm of the patient to let it face upward. –– Pronation: now let the palm face downward.

Pronation

Presence of tenderness, limitation, stiffness, and/or end of range stiffness may indicate presence of arthritis. Special Tests Golfer’s Elbow Test

This is to test for medial epicondylitis. Ask the patient to have their elbow and fingers flexed. Palpate the medial epicondyle with one hand, and grasp the patient’s wrist with the other hand, and then ask the patient to flex the elbow and wrist against resistance (Fig. 2.12). A positive test would be a complaint of pain or discomfort along the medial aspect of the elbow in the region of the medial epicondyle. Tennis Elbow Test

This is to test for lateral epicondylitis. Ask the patient to have their elbow and fingers extended. Palpate the lateral epicondyle with one hand, and grasp the patient’s wrist with the other hand, and then ask the patient to

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H. Almoallim et al. Lateral epicondyle (Humerus) Lateral epicondyle Radial head

Olecranon (Ulna)

O O M

L

L M L

O

O

M

L

M

Fig. 2.11  Some anatomical landmarks in the elbow joint. O: olecranon process, M: medial epicondyle, L: lateral epicondyle

extend the elbow and wrist against resistance (Fig.  2.13). A positive test would be a complaint of pain or discomfort along the lateral aspect of the elbow in the region of the lateral epicondyle. Elbow Flexion Test (Ulnar Nerve)

This test is to evaluate for cubital tunnel syndrome (Fig. 2.14). Ask the patient to hold their elbows fully flexed for 3 min with their wrists in neutral position and their shoulders adducted at their sides. The test is considered to be positive if paresthe-

sias were elicited within the ulnar nerve distribution of the hand.

2.5.3 The Shoulder Joint 2.5.3.1 First Step: The Anatomy (Fig. 2.15) The shoulder consists of three bones, four articular surfaces, muscles, and ligaments. The bones include clavicle, proximal humerus, and scapula. The articular surfaces include sternoclavicular joint, acromioclavicular joint, gleno-

2  Approach to Musculoskeletal Examination

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humeral joint, and scapulothoracic articulation. The muscles of shoulder are rotator cuff which includes supraspinatus, infraspinatus, subscapularis, and teres minor. The subscapularis muscle rotates the humerus internally, while the infraspinatus and teres minor rotate the humerus externally. Abduction of the humerus is accomplished by supraspinatus along with deltoid muscle. For the ligaments of the shoulder, they are the glenohumeral ligaments which are superior, middle, and inferior glenohumeral ligaments.

Fig. 2.12  A special test for medial epicondylitis

 pproach to Shoulder Pain A Shoulder pain represents either intrinsic or extrinsic pathologies. Intrinsic pathologies account for 85% of the cases and include traumatic, acute, and chronic causes. While extrinsic pathologies account only for 15% of the cases which represent referred pain that can be of cardiac, respiratory, gastric, or diaphragmatic in origin. The approach to patients present with shoulder pain should always start with: • History. • Physical examination. • Differential diagnosis.

Fig. 2.13  A special test for lateral epicondylitis: see text

Ulnar nerve

Fig. 2.14  Elbow flexion test

Start analysis of the shoulder pain by first determining the site of the pain. To assure accurate workup you may ask the patient to point one finger to the site of the pain by one finger. Shoulder pain can be classified into three categories according to the site: anterior, lateral, or posterior (Table 2.2). Lateral shoulder pain is the most common, and it is classical for rotator cuff tendinitis. Anterior shoulder pain is classical for glenohumeral arthritis. Posterior shoulder pain, which is the least common, usually represents referred pain. Following this step you need to cover other aspects of pain history to help you narrow the differential diagnosis according to the anatomical location and other important pieces of ­information you are going to collect from the patient. This should include the duration, nature, aggravating factors (with lifting, reaching or pushing) and

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Fig. 2.15  Anatomy of the shoulder joint

Ligament Acromion

Clavicle

Bursae

Rotator Cuff Musscle and Tendon

Labrum Glenoid Head of Humerus

Acromioclavicular Joint

Coracoid Process

Acromion

Clavicle

Subacromial Bursae

Sternoclavicular Joint

Supraspinatus Tendon Glenohumeral Joint Greater Tubercle Bicipital Groove Lesser Tubercle Subscapularis Tendon

Subscapularis Muscle

Scapula Sternum

relieving factors, radiation (shoulder pain that radiates past elbow can be due to cervical pathology), history of trauma, and sports activities. Past

medical history: diabetic and patients with thyroid diseases are at risk of developing adhesive capsulitis.

2  Approach to Musculoskeletal Examination Table 2.2  Differential diagnosis of shoulder pain Lateral shoulder pain Rotator cuff tendinitis. Adhesive capsulitis

Anterior shoulder pain Adhesive capsulitis Acromioclavicular pathologies Glenohumeral joint arthritis Biceps tendinitis Sternoclavicular injuries

Posterior shoulder pain – Rotator cuff tendinitis involving the external rotators – Referred pain • Diaphragm • Gall bladder • Perforated duodenal ulcer • Heart • Spleen • Apex of lungs

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• Ask the patient to abduct (ABD) shoulders to 90°, then supinate forearms (externally rotating (ER) the shoulders), continue abduction to 180°, do painful arc by bringing both shoulders to zero position again (if the patient develops pain, it indicates positive painful arc test suggestive rotator cuff tendinitis (RCT)), then ask patient to bring his hands behind the neck (ER + ABD), and then move hands backward over the back internal rotation (IR) and adduction (ADD) (IR + ADD). Then try bringing your thumbs on your back as high as possible (Apley’s scratch; Fig.  2.17), and finish with forward flexion and extension. • Shoulder elevation, protraction, retraction, and circumduction.

2.5.3.2 Second Step: The Approach It is always: • Inspection • Screening exam • Palpation • Range of motion • Special tests

Remember: • Always inspect anteriorly, laterally, and posteriorly Inspection • Skin: redness, scars, rashes. • Muscles: wasting, atrophy of deltoid (squaring sign). • Bones and joints: swelling particularly anteriorly obscuring the coracoid process area; this is in case of glenohumeral joint effusion, deformities (acromioclavicular (AC) joint, clavicle), scapula elevation (back), and asymmetry posteriorly (look at back exam for asymmetry). Screening Exam The aim is to screen for gross pathology. • It is basically the active ROM testing (Fig. 2.16).

Palpation • Remember: shoulder (or glenohumeral joint) effusion is usually detected anteriorly (this is not a common finding). • Palpate for bony and soft tissue structures: start with sternoclavicular joint (SC joint), then move to feel clavicle, AC joint, acromion, subacromial bursae (a lateral structure just below the acromion) (tenderness indicates RCT, greater trochanter (GT) (rotator cuff inserts here, you are feeling the capsular attachment of glenohumeral joint (GH joint) medially feel bicipital groove (long head of biceps), coracoid process where the short head of biceps inserts (it is painful!) • Palpate for crepitus by simply feeling over the joints while moving the shoulder. Range of Motion • The aim is to differentiate between intra-­ articular and extra-articular pathology. • In intra-articular pathology (arthritis), active and passive ROM are limited due to inflammation of the synovial membrane that moves during both active and passive ranges. There is usually effusion that might limit the ROM whether it was ­passive or active. Even if here was no effusion, the inflammation of the synovial membrane itself would limit the ROM passively and actively because of the pain.

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H. Almoallim et al. Circumduction

Flexion extension

Rotation

Abduction Internal (Medial)

External (lateral)

Fig. 2.16  Range of motion testing for shoulder joint Fig. 2.17 Apley’s scratch test

Adduction

2  Approach to Musculoskeletal Examination

• In extra-articular pathology (periarthritis), the active range is limited only. Here, there is synovial membrane inflammation to limit any kind of movement in the joint. Instead, there is pathology in structures around the joint like in RCT or subacromial (subdeltoid) bursitis. Here the active ROM will be limited but the passive is not. • You need to test two components to determine with accuracy the cause of the pain. • Active ROM was assessed during the screening exam. • For passive ROM: watch the location of your hands! • Place your right hand on the right shoulder over AC joint firmly. This is to stabilize the scapula in order to do isolated GH joint movement without scapular elevation. The other hand should hold the proximal forearm. • Do shoulder abduction up to 90°. This is a pure GH joint movement. Normally, there should be zero scapular elevation. Then do ER and IR, while the shoulder is abducted at 90°. Then adduct the shoulder back to zero position where the forearm and the elbow are just beside the body. Then do extension. Then remove your right hand on the right shoulder and do forward flexion. • You can assess ER + IR while at zero abduction with arms on the sides. • Repeat the same approach for the left shoulder with your left hand stabilizes the scapula over the left AC joint.

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findings in order to reach to a correct diagnosis. The diagnostic accuracy for majority of these tests is limited [5]. However, combining careful history taking skills with competent MSK examination findings should help improve the diagnostic accuracy at least to narrow your differential diagnosis rather than reaching an accurate diagnosis. For RCT

• Painful arc (as described above): from 120° to 60°. • Isometric resisted abduction while the arm is in zero degree. If there is pain developing, this could be due supraspinatus tendinitis. • Empty can sign: (Shoulder abducted 90° + forward flexion 30° away from the body on horizontal line + thumb down (IR)—supraspinatus) (Fig. 2.18). Infraspinatus and Teres Minor

• Isometric resisted ER (elbow flexed 90° with the arm at the side). • In the same position, you can assess isometric resisted IR for subscapularis tendinitis (Fig. 2.19).

Principle

To assess tendons you need to stretch the tendon (impingement) and/or stress it!

Special Tests Several MSK examination techniques will be described to assess for specific diseases affecting the shoulder joint. The emphasis should be as stated earlier on the combined evaluation for any patient with MSK complaints of the history and MSK examination

Fig. 2.18  Supraspinatus examination (“Empty can” test)

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Fig. 2.19  Infraspinatus and teres minor examination

Left off Test

This test is performed with isometric resisted IR while the patient adducting his shoulder and internally rotating it. Presence of pain while resistance may indicate subscapularis tendinitis (Fig. 2.20). Hawkins Impingement Sign

Shoulder horizontal adduction in 90° of flexion then adduct shoulder more with passive IR; this should reproduce symptoms (Fig. 2.21). Drop Arm Test (Fig. 2.22)

This is to test for complete supraspinatus tear. Sudden push to an abducted shoulder may result in arm drop if there is complete supraspinatus tear.

Fig. 2.20  Left off test

For AC joint:

• Painful arc (as described above): when it produces pain from 180 to 120. It is usually due to AC joint pathology rather than RCT. • There is another test called cross-body adduction test (Fig.  2.23). The patient simply performs horizontal adduction with the shoulder in flexion. This might reproduce pain due AC joint pathology. • For bicipital tendinitis: –– Speed’s test: resisted shoulder flexion at 90° with elbow extended and forearm supinated. –– Yergason’s sign (Fig. 2.24): resisted supination of the forearm with elbow 90° flexion. It

Fig. 2.21  Hawkins’ test for subacromial impingement or rotator cuff tendinitis

2  Approach to Musculoskeletal Examination

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has to be noted that rupture of the long head of biceps is rarely associated with significant weakness in elbow flexion. This is probably due to the fact that 85% of elbow flexion is from brachioradialis and short head of biceps rather than from long head of biceps. • For glenohumeral joint instability: • Anterior apprehension test (Fig. 2.25) (supine, 90 ABD and 90 ER, apply gentle forward pressure to posterior aspect of humeral head).

Fig. 2.24  Yergason test for biceps tendon instability or tendinitis

Fig. 2.22  Arm drop test

Fig. 2.25  Apprehension test for anterior instability

2.6

Fig. 2.23 Cross-arm test for acromioclavicular joint disorder

Musculoskeletal Examination of the Lower Limb Joints

The joints included in lower limb are ankle, knee, and hip. As in the upper limb section, there is a brief review of the important anatomical landmarks that should be mastered because it has clinical correlations. This will be referred to as the first step. Then an approach to pain originating from this joint will be discussed focusing on anatomical differential diagnosis. The second

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step will be to follow the stated approach in MSK examination with descriptions whenever it is necessary. Illustrations have been used sometimes as a self-explanatory toll.

2.6.1 Ankle Joint 2.6.1.1 First Step: The Anatomy • Bones of the Foot (Fig. 2.26) • Ankle and foot consist of 26 bones, 33 ligaments, and more than 100 muscles and tendons. The main structures are: • Bones: tibia and fibula and tarsal bones, which are calcaneus, talus, navicular, and cuboid, and three cuneiforms bones, five metatarsals, 14 Phalanges (proximal, intermediate and distal), and two sesamoid bones. • Joints: ankle joint, subtalar joint, metatarsophalangeal joints (MTP), and interphalangeal joints. • Ligaments: anterior and posterior tibiofibular ligament, anterior and posterior, talofibular ligament (ATFL and PTFL) and deltoid ligament (Figs. 2.27 and 2.28). Fig. 2.26 Bones of the foot

• Muscles and tendons: anterior tibialis, peroneal, extensors, and flexors muscles and tendons (Fig. 2.29).  pproach to Ankle Pain A The approach of any patient presents with ankle pain should include: • History. • Physical examination. • Differential diagnosis. The first step in any history of a joint pain is determining the site of the pain. This simply can be achieved by asking the patient to point out by one finger the site of the pain. The following steps should focus on comprehensive approach to pain analysis including duration, progression, aggravating and relieving factors, and history of trauma. Here, it is important to ask about and examine the patient’s shoes. RA classically affects MTPs and ankles. The first MTP joint can be affected classically by gouty arthritis. History of acute first MTP joint pain with swell-

Distal (3rd) phalanx Middle (2nd) phalanx Proximal (1st) phalanx

Forefoot Metatarsal bones

Medial (1st) cuneiform bone Middle (2nd) cuneiform bone Lateral (3rd) cuneiform bone

Lisfranc’s joint Midfoot

Navicular bone Cuboid bone

Talus

Calcaneus (os calcaneum)

Chopart’s joint

Hindfoot

2  Approach to Musculoskeletal Examination

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2.6.1.2 Second Step: The Approach

Posterior talofibular ligament

Anterior talofibular ligament

Calcaneofibular ligament

Fig. 2.27  Bones and ligaments of the ankle

It is always: • Inspection • Screening exam • Palpation • Range of motion • Special tests

Inspection Expose both ankles and feet and examine for asymmetry. Then follow the standard approach in inspection as it was explained at the introduction of this chapter. Remember: Always examine anteriorly, medially, laterally, and posteriorly.

Tibionavicular ligament Tibiotalar ligament Tibiocalcaneal ligament

Fig. 2.28  Bones and ligaments of the ankle

ing and redness is diagnostic for gout. Acute gout might mimic cellulitis as it may cause soft tissue swelling and redness as well. The first MTP joint can be involved chronically in osteoarthritis. The interphalangeal joints can be involved in psoriatic arthritis (PsA) that might give identical presentation to RA.  In addition, PsA might cause diffuse swellings in one or more than one toe called dactylitis. It may cause Achilles tendinitis and/or plantar fasciitis. Subtalar joint is classically affected in osteoarthritis. History of trauma-­related pain should direct the attention immediately to soft tissue problems (periarthritis rather than arthritis). Table 2.3 lists the possible differential diagnosis according to the site of the ankle and foot joints pain.

• Nail: evidence of psoriasis. • Skin: scar, redness, rashes, wart, ulcers, blister, calluses, corn, erythema, ecchymosis, change in color. • Muscle and tendons: wasting, atrophy, and swelling posteriorly for Achilles tendinitis. • Bone and joint: swelling, deformity (hammer toe, clawing or crowding of the toes, hallux valgus of forefoot), arch of the foot. Screening Exam • The aim is to screen for gross pathology. • It is basically the gait and active ROM testing. For any lower limb joint examined, gait examination is a mandatory step. • Ask the patient to walk in a straight line and then on toes and on heels. • Ask the patient to run a short distance (if it possible, this is of great value in assessing periarthritis). • Ask the patient to hop five times on each foot (if it possible) and then squat and stand from squatting position. • This quick screening tool actually has assessed the neuromuscular integrity for the lower limb. Walking on the toes, for example, assessed hyperextension of MTPs. If there is

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Achilles tendon Medial (and lateral) subcutaneous malleolar or ‘last’ bursae Retrocalcaneal bursae

Plantar aponeurosis (fascia)

Retroachilleal bursae

Subcalcaneal bursae

Fig. 2.29  Achilles tendon and plantar fascia Table 2.3  Differential diagnosis according to the site of the ankle and foot joints pain Anterior

Lateral

Medial Posterior Planter

–  Rheumatoid arthritis –  Gout arthritis –  Osteoarthritis –  Tendinitis –  Peroneal tendinitis, rupture, or subluxation caused usually by rheumatoid arthritis –  Tarsal tunnel syndrome –  Posterior tibial tendinitis –  Achilles tendinitis/rupture –  Retrocalcaneal bursitis Plantar fasciitis

arthritis in these joints, the patient will not be able to perform this. In addition, walking on toes assessed plantar flexion in ankle joints and extension of knees and hips. Squatting and standing from squatting position have assessed, in addition of joints, the strength of proximal muscles. Walking on heels is an excellent screening for plantar fasciitis. The different steps applied in this screening exam assessed as well almost all the nerve roots for the lower limbs. Palpation The major aim is to look for evidence of arthritis in the form of warmth, effusion, and joint line tenderness. Tenderness might be felt laterally and/or medially if there is ligamentous pathology:

• Palpate skin and soft tissue (muscles, ligaments, and tendons). • Determine joint lines and palpate for tenderness: –– Ankle joint: (tibia, fibula, and talus joint) perform plantar flexion/dorsiflexion to locate joint line or just medial to the strong tendon of tibialis anterior as it passes over the ankle joint to be inserted at the base of first metatarsal bone. –– Subtalar joint (talocalcaneal joint): perform inversion/eversion or adduction/ abduction of the midfoot to locate this joint. Usually, it can be palpated below and anterior to lateral malleolus. –– MTPs: Press firmly and intermittently with your thumb and index finger over these joints to illicit tenderness. It is much more reached from plantar aspect than the dorsal aspect of the feet. –– Medially: Palpate the big toe at the site of the first MTP, and move along the first metatarsal to feel the metatarso-cuneiform joint. Palpate the navicular tubercle, the head of the talus, and the medial malleolus. –– Laterally: Start palpating the fifth metatarsal bone to feel the styloid process, and then reach the cuboid bone to the calcaneus. Palpate for the peroneal tubercle to the lateral malleolus.

2  Approach to Musculoskeletal Examination

–– Posteriorly: Feel the Achilles tendon and follow its insertion at the calcaneus for any tenderness. Just lateral and medial to the insertion of the Achilles tendon, feel for retrocalcaneal bursitis on both sides (lateral and medial) of the tendon. –– Inferiorly (plantar aspect): Feel for tenderness at the insertion of plantar fascia under the medial side of the heel. In assessing dorsiflexion: the knee must be flexed for proper evaluation

Range of Motion (Fig. 2.30) • You have done active ROM in your screening exam, but you may repeat active ROM now for detailed examination. • Examination includes passive and active ROM for the following actions: plantarflexion, dorsiflexion, inversion, and eversion of the foot and flexion and extension of the toes, particularly the big toe. • Hold the distal leg with one hand while the knee in a flexed position. Then hold the feet from central position just between the ankle and the MTP joints. Now, perform slowly full dorsiflexion (20° from neutral position) by bringing the ankle to the leg, and then push the ankle away from the leg for plantarflexion (50° from neutral position). Now, grasp the feet and perform inversion and eversion. In the same position, you may perform midfoot ad duction and abduction as well. Note any limitation of movement, tenderness, stiffness, and/ or end range stiffness. Special Tests • Squeeze test (Fig.  2.31): This test aims to stress the MTPs looking for tenderness due to arthritis. Simply squeeze the sides of MTP joints at the level of the heads of phalanges. • Peroneal subluxation test: • This is to assess the peroneus longus tendon rupture or instability. Ask the patient to sit down and actively dorsiflexes and everts the foot against resistance; and simultaneously palpate

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• •

• •



the peroneal tendon posterior to the distal fibula. Pain, clicking, or sensation of instability may indicate subluxation of the peroneal tendon. This test is abnormal when 3–5 mm translocation is present compared with the opposite side. The anterior drawer test (Fig. 2.32): Evaluate stability of the anterior talofibular ligament (ATFL): stabilize the anterior portion of the distal tibia and fibula with your hand, and use your other hand to cup the heel of the patient foot and pull it toward yourself. The inversion stress test (Fig. 2.33): Evaluate the stability of the lateral ligament complex (the ATFL and the calcaneofibular ligament (CFL)). –– Stabilize the anterior portion of the distal tibia and fibula with your hand, and use your other hand to cup the heel of the patient foot. –– The ATFL is evaluated by maximally plantarflexing the ankle and then inverting the rear foot. –– The CFL is evaluated by maximally dorsiflexing the foot and then inverting the rear foot. –– The test is considered abnormal when 10°– 15° more inversion is present, compared with the opposite side. Test for Morton’s neuroma: Grasp consecutive metatarsal heads and compress them together. If a click, as well as reproduction of the patient’s pain, occurs, a Morton’s neuroma should be suspected. Thompson test (Fig. 2.34): Ask the patient to lie in prone position with the foot hanging off the table, and then squeeze the gastrocnemius muscle. If the foot does not plantarflex, rupture of the Achilles tendon must be considered.

2.6.2 Musculoskeletal Examination of the Knee Joint 2.6.2.1 First Step: The Anatomy (Fig. 2.35) The bones and articulation of knee joints consists of four bones, which are femur, tibia, fibula, and patella. There are three articulations: medial tib-

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Fig. 2.30  Range of motion of the ankle joint

a

Dorsiflexion

Plantar flexion

b

Eversion

Inversion

2  Approach to Musculoskeletal Examination

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iofemoral, lateral tibiofemoral, and patellofemoral articulation. The knee joint has many bursae: in the anterior aspect suprapatellar bursae, prepatellar bursae, and superficial and deep patellar bursae and in the medial aspect pes anserine. Cartilage and ligaments of the knee are anterior and posterior cruciate ligaments, medial and lateral collateral and medial and lateral menisci. Approach to Knee Pain The approach of any patient presents with knee pain should include: Fig. 2.31  Squeeze test

Fig. 2.32  Anterior drawer test

• History. • Physical examination. • Differential diagnosis.

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The first step is to determine the site of the pain. This is achieved by asking the patient to point by one finger to the site of the pain. In some condition like anserine bursitis, the location of the pain is totally away from joint line. Determining the site of the pain is extremely an important step for reaching accurate diagnosis. Detailed history including duration, progression, and aggravating and relieving factors should follow. History of trauma should be clearly outlined particularly if it was sports related. There are many soft tissue structures that can be affected with traumatic injuries. The knee is the most common joint involved in septic arthritis. Symptoms suggestive of an infectious process like fever should be obtained as well. The knee as well is a common joint in osteoarthritis and crystal deposition diseases (like pseudogout). Table 2.4 provides a classification of the knee pain according to the site of the pain and its differential diagnosis.

2.6.2.2 Second Step: The Approach

Fig. 2.33  The inversion stress test

It is always: • Inspection • Screening exam • Palpation • Range of motion • Special tests

Fig. 2.34  Calf squeeze test

Ankle plantarflexes

No movement

2  Approach to Musculoskeletal Examination

Collateral ligament

45

Anterior cruciate ligament

Femur Femur

Patella

Lateral meniscus

Posterior cruciate ligament

Tibia Tibia

Fibula

Anterior cruciate ligament

Medial meniscus

Fig. 2.35  Anatomy of the knee Table 2.4  A classification of the knee pain according to the site of the pain and its differential diagnosis Anterior

Common –  Arthritis –  Osteoarthritis –  Prepatellar bursitis –  Jumper’s knee (patellar tendinitis)

Lateral

–  Iliotibial band tendinitis

Posterior

–  Popliteal cyst (baker’s cyst) –  Pes anserine bursitis

Medial

Not to be missed –  Ligamentous injury –  Tibial apophysitis (Osgood-Schlatter lesion) –  Patellofemoral pain syndrome (chondromalacia patellae) –  Lateral collateral ligament sprain –  Lateral meniscal tear –  Posterior cruciate ligament injury –  Medial collateral ligament sprain –  Medial meniscal tear

Inspection • Skin: redness, scars, rashes. • Muscles: wasting (note medial fibers of quadriceps), atrophy.

• Bones and joints: swelling, deformities – genu varus (common in osteoarthritis of the knee joint) and genu valgus deformities. Screening Exam • The aim is to screen for gross pathology. • It is basically the gait and active ROM testing. • Ask the patient to walk and comment if the gait is normal or abnormal. • Ask the patient to walk on toes, heels, and squat and stand up from the squatting position (see details in ankle joint exam above). Palpation • The major aim is to look for evidence of arthritis in the form of warmth, effusion, and joint line tenderness. • Palpate for tenderness over the patella, patellar tendon, suprapatellar bursae, prepatellar bursae (housemaid knees), anserine bursae (medially below joint line, just 2 cm from tibial tuberosity), and tibial tuberosity (where the

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patellar tendon inserts, it can be tender in patellar tendinitis). • Palpate for crepitus, osteophytes, and popliteal cyst. • The maneuvers used to detect effusion: 1. Bulge sign: –– Milk the knee with the palmar or dorsal aspect of your fingers 1–3 times from the tibial side to medial side of the femur. Wait for a few seconds. –– Now with your fingers, milk the fluid down from the femur side to the tibia laterally. Note the bulge of fluid on the medial side. This method detects mild effusion. 2. Patellar tap test: –– Compress the suprapatellar pouch with one hand. With the tips of the fingers of the other hand, give a sharp downward push on the patella. Feel the patella’s clunk against the femoral condyles. This method detects moderate effusion. 3. Balloon sign: –– Compress the suprapatellar pouch with one hand. Place the thumb and index (or long) finger of the other hand on either side of the patella at the level of the joint line. Now if you press with these fingers, you should feel the fluid pushing away the other hand. This test is positive for large effusion.

Range of Motion The aim is to differentiate between intra-articular and extra-articular pathology. • In intra-articular pathology (arthritis), active and passive ranges of motion are limited (see explanation in shoulder joint exam). • In extra-articular pathology (periarthritis), the active range is limited only. • You need to test two components: active and passive ROM. • Ask the patient to bring both heels toward the pelvis as much as possible (flexion), and then ask the patient to put his knees flat on the bed (extension). • For passive ROM testing, ask the patient to relax. With one hand covering the entire knee anteriorly and the other holding the heel, flex the knee and then extend it. You should ­comment on tenderness, stiffness, end of range stiffness, and/or limitation of movement. Special Tests • The aim is to look for the integrity of menisci and ligaments around the knee. • For menisci integrity, you can use the McMurray test (Fig. 2.36): hold the knee with one hand, while the patient is in supine position. Bring the knee to full flexion. Now, extend the knee slowly with applying valgus stress from the lateral aspect of the knee you

McMurray test

Valgus sbress and extension External rotation

Apley compression test

Fig. 2.36  McMurray test and Apley compression test

2  Approach to Musculoskeletal Examination

are holding with your hand, while the other hand is externally rotating the knee from the ankle. The test is considered positive if there is pain and/or popping sound. • Apley’s compression test: here the patient lies in prone position with the knee being examined flexed at 90°. You should stabilize the knee by placing your leg pressing over posterior aspect of the patient’s thigh. Apply now compressing pressure over the knee from the ankle with external rotation force. The test is considered positive if it produces pain. • For cruciate ligaments (CL), you can use the anterior drawer test (Fig. 2.37): you should sit on the patient’s feet for stabilization the flexed knees to around 90°. Place your hands on the tibial plateau from medical and lateral aspects, and then try to push tibia anteriorly over the femur toward your side (anterior drawer test) or posteriorly (posterior drawer test). Any displacement particularly when compared with the other knee is considered positive for cruciate ligament instability. The Lachman test: the patient here is in supine position. You should place one of your hands above the knee joint line with a good grasp, while the other is just below the knee joint line. In around 20–30° of

Anterior drawer test

47

passive knee flexion, try to apply contradicting forces by two hands; one pushes anteriorly while the other pushes posteriorly. Any excessive displacement is considered positive (Fig. 2.38). The validity of these tests has been questioned [5]. In general, this test is more sensitive than the anterior drawer test [4]. • For collateral ligaments, you can apply valgus and varus stresses, while the knee is held in 40–70° of flexion to assess for medial and lateral collateral ligaments, respectively. With positive result, there will be laxity and wide openings of the joint.

2.6.3 Musculoskeletal Examination of the Hip Joint 2.6.3.1 First Step: The Anatomy (Fig. 2.39) The hip joint is formed by the articulation between the round head of the femur and the acetabulum. It is a ball and socket joint with one part, the acetabulum, which is fixed in the body. Three bones compose the acetabulum: Ilium, ischium, and pubis. Femoral neck, Greater Trochanter (GT), and lesser trochanter are bony structures of anatomical significance. Femoral neck is vulnerable site for osteoporotic fractures. This site is used to measure bone mineral density to diagnose osteoporosis. The insertion of hip abductors and extensors are at the GT. While the hip flexor (iliopsoas) inserts at the lesser trochanter. An important bursae covers the GT which can be inflamed and cause symptoms. Symphysis pubis is a fibrocartilage that can cause symptoms.

Lachman test

90°

20°-30°

Fig. 2.37  Anterior drawer test

Fig. 2.38  Lachman test

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Fig. 2.39  Anatomy of the hip joint Illium

Head or femur

Greater trochanter

Neck of femur

Pubis

Ischium

 pproach to Hip Pain A It is important to determine the site of pain. This is an essential step in the history of any joint pain. True hip joint pain (due to arthritis of head of femur articulating with the acetabulum) can be felt only anteriorly in the groin region. In the case of hip arthritis, you can expect to find, in addition to groin pain, severe limitation in the ROM actively and passively. Hip joint is a deeply seated joint; for this reason aspiration is always performed under fluoroscopic or US guidance. Pains that felt elsewhere in the hip region could be due other structures around the hip joint and still called by patients as “hip pain.” Trochanteric bursitis is a classical example of a lateral hip pain in moderately obese female. Here there is tenderness by palpation in the lateral hip, and the active adduction and/or abduction may be painful, but usually the passive ROM is intact. In meralgia paresthesia (lateral cutaneous nerve entrapment), there is usually pain in the anterolateral hip region with entirely normal ROM.  There are many structures posteriorly that can cause pain. Sacroiliac joint gives rise to posterior hip pain and usually referred to by some patients as buttock pain. Lumbar radiculopathy is another differential diagnosis. The patient should be asked

then to point to the site of hip pain by one finger to exactly determine it. Table 2.5 summarizes the most important differential diagnosis of hip pain according to its site.

2.6.3.2 Second Step: The Approach

It is always: • Inspection • Screening exam • Palpation • Range of motion • Special tests

Inspection • You should start inspection from standing position and inspect anteriorly, laterally, and posteriorly. Then you can continue your examination after screening exam and palpation, while the patient is in supine position. • Standing: –– Back: Skin: redness, scars, rashes. Muscles: wasting, atrophy.

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49

Table 2.5  Classification of the hip pain according to the site of the pain and its differential diagnosis Site of the pain Common Anterior Arthritis Synovitis Osteoarthritis Chondropathy Osteitis pubis Lateral Trochanteric bursitis Greater trochanter pain syndrome Posterior Sacroiliac joint disease, Lumbar radiculopathy Inferior hip joint osteophytes associated with hip arthritis

Less likely Stress fracture Hip joint instability

Referred pain from lumbar spine

Bones and joints: assess symmetry and pelvic obliquity – inspect posterior superior iliac spine (PSIS) (dimples of Venous) as they should be align to one level. Asymmetry may give clues to cases with chronic low back pain without apparent etiology. Inspecting gluteal folds, tip of scapula can assess symmetry. –– Lateral: inspect for lumbar lordosis and possible swelling or redness over greater trochanter. –– Anterior: symmetry can be assessed by inspecting anterior superior iliac spine (ASIS). Rarely, fullness in the groin region may indicate hip arthritis. However, significant hip joint pathology can occur without apparent swelling. Inspect also for rashes, redness, and scars. Screening Exam • Apparent leg length: from xiphoid cartilage or umbilicus to medial malleolus • True leg length: from ASIS to medial malleolus

• The aim is to screen for gross pathology. • It is basically the gait and active ROM testing. • Note position: external rotation (ER) indicates hip joint pathology as internal rotation (IR) is lost first in arthritis. • See ankle joint exam above for details of gait assessment. Simply you should ask the patient

Not to be missed Synovial chondromatosis Avascular necrosis (AVN) of the head femur Slipped capital femoral epiphysis (SCFE) Tumor Legg-Calve-Perthes disease Fracture of neck of femur Nerve root compression Tumor

to walk/turn/walk on toes/on heels/squat (if possible) and stand from squatting position. This is a comprehensive evaluation of the neuromuscular integrity of the lower limb. Walking by itself is a good screening for hip flexion and extension. Squatting position is a good screening again for hip flexion and extension. • Assess Trendelenburg sign: ask the patient to stand on the affected side that has classically hip joint arthritis (diseases like osteoarthritis) with week hip abductors and extensors. Then ask the patient to raise the normal side. Normally, the pelvis in the unsupported side will be raise due to the tone of strong muscles from the other supported side. In this sign and because of weakness of hip muscles from arthritis, the muscle tone here cannot support the pelvis in the other unsupported side, and this will result in pelvis drop in the unsupported side with positive sign. Trendelenburg gait is basically the same explanation, but when the patient needs to walk, bending laterally toward the supported side will raise the dropping unsupported pelvis producing the classical waddling gait with bilateral involvement of both hips. • Note the type of gait (Fig. 2.40). Palpation • You can start palpation, while patient is still in standing position. • Back: palpate paraspinal muscles, sacroiliac joint (SI joint) (1 inch medical + inferior to PSIS), iliac crest, and ischial tuberosity (IT)

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Fig. 2.40  Types of gait: normal (a) and abnormal (b)

• •

• •

a

Normal

(you may ask the patient to step on a stool using the limb under examination), feel GT, and feel sciatic nerve between the IT and GT. Lateral: palpate trochanteric bursae (Fig. 2.41). Anterior: palpate groin region – lymph nodes, pulses, hernia, ASIS, hernial orifice, pubic tubercle (where adductor longus originates), symphysis pupis  – note any discrepancies in leg length. You may continue your palpation now, while the patient is in supine position. Quick screening: “frog” leg position—external rotation (ER) + abduction (ABD) + knee flexion—then compare both sides. In this position you may feel adductor longus tendon

b

abnormal

by asking the patient to adduct the hip against resistance and then just follow the adductor longus tendon until its origin from the pubic tubercle. Eliciting pain here may give you the diagnosis of adductor longus tendinitis. • Flex hips and knees then extend them and look for leg length discrepancy. Range of Motion • You have done active ROM in your screening exam for two important hip movement flexion and extension. Now, you need to do comprehensive assessment of ROM (Fig. 2.42). • In supine position: ask the patient to flex hip as much as possible; you may combined hip

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Fig. 2.41 Trochanteric and iliopsoas bursae

Apohysis of anterior superior iliac spine

Femoral head epihysis

Trochanteric bursae

IIliopsoas bursae

Apophysis of ischial tuberosity

Neutral position

Flexion with knee bent

Hyperextension

Flexion with knee extended

Passive extension in a pron position

Fig. 2.42  Range of motion testing for hip joint

Adduction

Abduction

Rotation in flexion

Internal rotation in a setting position

External rotation

Permanent flexion (flexor contracture)

Internal rotation

52

and knee active flexion by asking the patient to bring the knee to abdomen. Back to supine position and ask patient to abduct the hip laterally to as much possible and return to each hip one at time and ask the patient to cross midline. This is adduction. Back to supine position, and ask the patient to bring both plantar surfaces of both feet together facing each other with both knee flexed. This is external rotation (ER), and it is called “frog” leg position. The opposite of this position is the assessment of internal rotation (IR). The other position for active ER and IR is while patient is sitting at the edge of the bed with the knees and hips flexed. Bringing the leg away is IR and toward the midline is ER. The same technique can be done while the patient is supine. Extension can be assessed while the patient is in lateral decubitus position with the hip moved posteriorly. • Active: Flexion 120° –– Abduction 50° –– Adduction 30° –– Frog leg (for ER) 45° –– Opposite of frog leg (for IR) 35° –– Or in prone position: do active ER + IR –– Assess ER + IR through leg rolling while hips are extended. • In lateral decubitus position: you may palpate trochanteric bursae and perform active extension 30°. • The passive ROM can be assessed, while the patient is in supine position. Flex the hip and try to bring it to patient’s abdomen. Back to neutral position, and while putting one hand on the pelvis, take the hip to abduction, and use the same technique for the other hip. Perform passive adduction by crossing midline. For ER, flex hip and knee to 90°, then hold knee with one hand and the heel with the other hand, and then bring heel medially. For IR: bring heel laterally. Assess passive extension in lateral decubitus position or in prone position. Special Tests • Hip fixed flexion deformity: • Thomas test: bring both knees to patient’s abdomen and then extend one hip. If it failed

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Fig. 2.43  Testing for piriformis syndrome

• • • • • • •

to extend fully, there is fixed flexion hip deformity. Trochanteric bursitis: Tenderness over GT with pain elicited by resisted abduction. Radiculopathy: Straight leg raising test and slump test (see back exam). Piriformis syndrome: Resisted abduction while hip is flexed at 90° and adducted (Fig. 2.43). Tightness in iliotibial band (Ober’s test): In lateral decubitus, neutralize hip and knee at 90°, and then abduct hip: a tight iliotibial band prevents the hip from adducting passively (Fig. 2.44).

2.7

Back Examination

2.7.1 First Step: The Anatomy • The spine represents the axial skeleton of the back, and it is composed of 32–33 small bones, called vertebrae (7 cervical, 12 thoracic, 5 lumbar, 5 fused sacral, and 3 or 4 coccygeal) (Figs.  2.45 and 2.46). The vertebrae bear the majority of the body weight and transfer it to lower limbs and also provide protection and support to spinal cord. A typical

2  Approach to Musculoskeletal Examination

53

ing the vertebral foramina through vertebral notches of the adjacent pedicles. The spinal nerves exit the intervertebral foramina in relation to vertebral levels as the following: nerves of C1-C7 exit superior to the pedicles of the same-numbered level, C8 nerve inferior to C7 pedicles, and then T1 and below exit inferior to the pedicles of the same-­numbered level. • Different injuries and diseases may affect the components of spine and its surrounded paraspinal muscles resulting in back pain (Figs. 2.48 and 2.49) (See Chap. 6). Fig. 2.44  Ober’s test

vertebra is consisted of anterior body and posterior arch enclosing the vertebral canal where the spinal cord extends from the brain to the area between the end of first lumbar vertebra and top of second lumbar vertebra (L1 or L2 vertebral levels). Between each vertebra is a cartilaginous joint, called intervertebral disc. The discs limit the movements between the individual vertebrae and also act as a shock absorber (Fig. 2.47). The vertebral bodies are strictly attached to the intervertebral discs by two main ligaments: anterior and posterior longitudinal ligaments. Each pair of vertebrae is also connected by a synovial joint called facet joints. This is formed by the inferior articular process of one vertebra joining the superior articular process for the vertebra just below it. The facet joints give the spine its flexibility as there are two facet joints between each pair of vertebrae, one on each side. While the joints allow flexibility, the mobility of the spine is provided by the surrounded paraspinal muscles extended laterally along the spine. • In the vertebral foramen posteriorly, the spinal cord extends down to the end of the second lumbar vertebra. Below this level, the spinal canal forms a group of nerve fibers, called the cauda equina. This group of nerves goes to the pelvis and lower limbs. Attached to each segments of the spinal cord, there is a pair of 31 spinal nerves exit-

2.7.2 Second Step: The Approach It is always: • Inspection. • Screening exam. • Palpation. • Range of motion. • Special tests.

2.7.2.1 Inspection You may start your examination by explaining to your patient the steps of your exam. After proper exposure, start your inspection, while the patient is standing. You may ask one of the family members to be around. Always inspect the patient posteriorly, laterally, and anteriorly. • Alignment: you should be familiar with the normal alignment of the spine. This is to help inspect for abnormal alignment that may give rise to chronic back pains: kyphosis, scoliosis, and exaggerated or lost lumbar lordosis. In patients with ankylosing spondylitis (AS), lumbar lordosis is usually lost from spondylitis. This also can be lost due to severe muscle spasm over the lower back. • Skin: Inspect for erythema, hair patch, café au lait spots, nodules, and/or scars. • Muscles: wasting, atrophy.

54 C1 2 3

a

C1 ventral root

4

C2 ventral root

5 6 7 8

Cervical enlagement

T1 2 3

T1 dorsal root

4 5 6 7

T6 dorsal root

8 9 10 Lumbar enlagement

11 12

L1 dorsal root

L1 2 Conus medullaris 3

S1 dorsal root

Filum terminate 4

Coccygeal nerve 5 S1

c

2 3 4 5 Coc. 1

b S1-5

Spinal canal diameter (mm)

Fig. 2.45  Bones of the spine [6]

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30

25

Width

20 Depth 15

0

2 3 4 5 6 7 2 7 12 1 2 3 4 5 Cervical

L2-3

C7 T10 T3 C1

C2

C3

S1

L3

Thoracic Spinal level

Lumbar

2  Approach to Musculoskeletal Examination

55

Fig. 2.46  Structures of lateral spine

Superior articular facet

Articular facet

Vertebral body

Head of rib

Spinous process

Transverse proces

Inferior articular facet

a

b

1 6 5

3 4

Vertebral artery

1

4 3

2

3

7

1 Superior articular process 2 Posterior tubercle 3 Costotransverse bar of transverse process 4 Anterior tubercle 5 Body 6 Pedicle 7 Inferior articular process

Fig. 2.47  Structure of a vertebra

• Symmetry: check symmetry of the back by assessing whether tips of scapulae are at one level or not. Also for the iliac crests and gluteal folds. Inspect PSIS (dimples of Venous) as they should be align to one level. You may ask the patient to flex the hip and observe while you are standing behind the patient the symmetry and whether the asymmetry is corrected or not.

2.7.2.2 Screening/Gait Assessment • Gait: straight walking while watching for abnormal flexion (suggestive of spinal stenosis or facet joint pathology), abnormal extension (suggestive of disc pathology), or Trendelenburg gait (Fig. 2.50). • Screening for neurological integrity: walking on toes (L5, S1) and then on heels (L4, L5), knee extension (L3, L4); then ask patient

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Fig. 2.48  Some surface anatomy landmarks Erector spinae muscles Iliac crest

to squat and stand from squatting position, hip flexion (L2, L3), and hip extension (L5, S1). • Position: watch as patient changing position. • Asses Trendelenburg sign (see hip joint exam): the patient stands on affected side and then raises the normal side, and in a positive test, the unsupported side will drop. • Note the type of gait: normal gait passes through two phases stance and swing phases. The stance phase consists of heel strike, mid-­ stance, and toe off. The swing phase has an acceleration and deceleration components. A common gait abnormality in rheumatology is antalgic gait which is simply short stance phase gait due to pain in one of the lower limb joints.

2.7.2.3 Palpation Start palpation while patient is in prone position. Palpate spinous processes over the midline from cervical down to sacral regions (Fig. 2.51). You may percuss to illicit severe tenderness that might indicate discitis. You may palpate now the paramedian spinal structures including muscles (for tenderness and/or spasms as majority of low back pain is caused by muscle strain and/or spasm), interspinous or supraspinous ligaments, and facet joints. Keep in mind the low specificity of these

L4-5 intervertebral joint

Sacroiliac joint

techniques. You may palpate now iliac crests for tenderness suggestive of enthesitis a hall mark feature of spondyloarthritis, while palpation observe any skin and/or soft tissue fluid collection suggestive of an abscess. Palpate the dimples of Venus at the level of S2 as the sacroiliac joints lie beneath them. It can be severely tender in sacroiliitis. You may ask the patient to stand and put his feet on a chair or a stool and you can posteriorly identify by palpation two bony prominences: the ischial tuberosity medially and the GT laterally. The sciatic nerve can be palpated in the area between these two. Severe tenderness can be illicit in patients with sciatica and/or piriformis syndrome.

2.7.2.4 Range of Motion This can be assessed by asking the patient to perform the following: • Flexion: ask patient to bend forward with extended knees and bring fingers to floor. The distance between the long finger and the floor can be documented and used to follow up response of treatment in cases of spondylitis. • Extension: stabilize the pelvis and ask the patient to extend the back as much as possible. Figure 2.52 demonstrates ROM of cervical spine.

2  Approach to Musculoskeletal Examination Posterior view

57 Left lateral view

Atlas (C1)

Atlas (C1)

Axis (C2)

Axis (C2)

Cervical vertebrae

Cervical curvature C7 T1

Thoracic

C7 T1

Thoracic curvature

vertebrae

T12

T12

L1

L1

Lumbar

Lumbar

vertebrae

curvature L5 L5

Sacrum (S1-5)

Sacrum curvature Coccyx

Fig. 2.49  Vertebral column [7]

Coccyx

58 Fig. 2.50 Trendelenburg sign: (a) normal response. (b) Abnormal response with drop of the pelvis in the unsupported leg due to weakness in the opposite (supported leg) muscles. This will result in Trendelenburg gate

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a

b

• Lateral flexion: The patient may stand against the wall and bend laterally and trying to slide the fingers to fibula. The distance between the long finger and the fibula or the floor can be documented and used in monitoring response to therapy in spondylitis (Fig. 2.53). • Thoraco-lumbar rotation: This is best examined while the patient is sitting at the edge of the bed. Ask the patient to turn to the side without moving the pelvis as much as possible; up to 70° can be achieved normally. This movement can be checked passively to examine for any tenderness, stiffness, limitation, and/or end of range stiffness (Fig. 2.53).

2.7.2.5 Special Tests

Fig. 2.51  Areas for palpitation

Straight Leg Raising Test (SLRT) (Fig. 2.54) This is to test for radiculopathy of L5-S1. Keep the patient in supine position with extended hip and knee. Then flex the hip slowly until a complaint of shooting radicular pain or tightness is

2  Approach to Musculoskeletal Examination

59

a

b Flexion

Extension

Rotation

c

Lateral flexion

Fig. 2.52  Range of motion of cervical spine

reached. The test can be considered positive with classical radiation of the pain at 30–70° of leg elevation. Just lowering the examined leg few degrees before the pain appeared and then passive dorsiflexion of the ankle is performed as a confirmatory technique. Symptoms should recur in strongly positive test (Fig. 2.55). Slump Test (Fig. 2.56) This test is performed again to look for radiculopathy at L5-S1. The patient should be sitting at the edge of the bed with both arms stabilized over the back. You should flex the outstretched extended leg to be examined by holding the toes or the ankle, and at the same time, ask the patient to flex the neck and bring the chin to the chest

wall. A shooting radicular pain might result from this stretch indicating a positive test. Sacroilliac Joints Exam Patrick test and compression test: perform (FABER test (flexion abduction external rotation test)) Fig. 2.57. Flex the hip, abduct, and externally rotate it while the other leg in extended. Then compress over the iliac crest of the extended leg and over the knee of the flexed leg. A positive test produces pain in the sacroiliac joint of the leg being tested. Modified Schober’s Test This test is to assess for limited lumbar spinal flexion. Mark the PSIS (dimple of venous) by

60 Fig. 2.53  Range of motion of thoraco-­ lumbar spine. (a) Flexion and extension. (b) Rotation. (c) Lateral extension

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a Flexion

Extension

Lateral extension

b

c

Rotation

drawing a line connecting both points. At the center of this line, mark a point. Using a tape measure placed at the center point, mark 5 CM below this line and 10 CM above this line. Then ask the patient to bend forward without bending the knees. Now, measure the distance between the points. The distance between the two points should be more than 15 by 5 additional CM (≥ 20 CM). Any movement that results in less than this is considered abnormal. Neurological Exam Detailed neurological exam should be conducted. The motor findings are reliable and should direct further intervention with the patient. One of the simple tests to perform is muscle bulk by a tape measure from a fixed bony prominence. More than 1 CM difference is considered abnormal for

patients presenting with radicular symptoms. Rectal tone (S3,4,5) should be also performed in the right clinical settings. Fig. 2.58 represents a quick tool to examine in brief the roots of the lower limb. This quick approach includes examining the power of the following movement (note that it goes for simplicity from 2 to 5): hip flexion (L2), knee extension (L3), ankle dorsiflexion (L4), big toe extension (L5), and ankle plantar flexion (S1). This is in addition to sensory exam as shown in Fig. 2.59. Sensory level is an important clinical finding to be determined in the right clinical setting in order to decide on further intervention and follow-up. Figure  2.60 summarizes the steps of back examination. Acknowledgments  The authors are grateful for the help provided by Mohamed Cheikh, Mawaddah Al hadeedi, Abdulrahman Kabli, Rehab Simsim, and Waleed Hafiz in composing this chapter.

2  Approach to Musculoskeletal Examination

61

a

b

c

d

Fig. 2.54  Straight leg raising test

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a

b

Fig. 2.55  Another approach to test for radiculopathy at L5-S1 Fig. 2.56  Slump test

Fig. 2.57  FABER test (flexion abduction external rotation test)

2  Approach to Musculoskeletal Examination L2

63

L5 L4 S1

L2- Hip flexion L3- Knee extension L4- Ankle dorsiflexion L5- Big toe extension S1- Ankle toe extension

L3

Fig. 2.58  Quick tool to examine in brief the roots of the lower limb

Fig. 2.59  Levels of principle dermatomes of the lower limb

S4

T12 L1 L2 L3 L4 L5

S5

S2

S1

T10 T11 L1 L2 L3

S3 S1 S2

L4

L5

S1 L5

T12

S2,S3

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Gait

Inspection

Palpation

Range of Motion

Special Test

• Gait: straight walking while watching for abnormal flexion (stenosis or facet joint), extension (disc), or Trendelenburg gait. • Screening: walking on toes then on heels. • Position: watch as patient changing position.

• Alignment: Kyphosis, scoliosis, or loss or exaggerated lordosis. • Skin: Erythema, hair patch, Café au lait spots, nodules, and or scars. • Inequality: watch for iliac crest and pelvic inequality => at the level of L4-5: ask patient to flex his/her hip. • N.B: Always inspect the patient posteriorly and laterally.

• Examine the patient in the prone position. • Spinous processes: tenderness or defects. • Inter-spinous ligament. • Supraspinous ligament. • Paraspinal muscles. • Iliac crest: tenderness (Spondyloarthritis) or nodules. PSIS –Sacroilliac joint -S2 • Ischial tuberosity -Sciatic nerve -Greater trochanter.

• Flexion: finger-floor • Extension: stabilize the pelvis and measure the distance • Lateral flexion: Finger-fibula (against the wall). • Tohoraco-lumbar rotation: 70º normally.

• Straight leg raising test (SLRT) • Slump test • Sacro-illiac joints exam: Patrick test and compression test • Modified Schober's test • Neurological exam: Muscle bulk by tape (Radiculopathy) and rectal tone (S3,4,5)

Fig. 2.60  Summary of back examination

2  Approach to Musculoskeletal Examination

References 1. Woolf AD, Walsh NE, Akesson K. Global core recommendations for a musculoskeletal undergraduate curriculum. Ann Rheum Dis. 2004;63(5):517–24. 2. Woolf AD, Pfleger B.  Burden of major musculoskeletal conditions. Bull World Health Organ. 2003;81(9):646–56. 3. Almoallim H, et al. Sensitivity of standardised musculoskeletal examination of the hand and wrist joints in detecting arthritis in comparison to ultrasound findings in patients attending rheumatology clinics. Clin Rheumatol. 2012;31(9):1309–17.

65 4. Solomon DH, et al. The rational clinical examination. Does this patient have a torn meniscus or ligament of the knee? Value of the physical examination. JAMA. 2001;286(13):1610–20. 5. Hegedus EJ, et  al. Physical examination tests of the shoulder: a systematic review with meta-analysis of individual tests. Br J Sports Med. 2008;42(2):80–92; discussion 92 6. Yoganandan N, Dickman CA, Benzel EC. Spine surgery. Copyright © 2012, Copyright © 2012, 2005, 1999 by Saunders, an imprint of Elsevier Inc. 7. Hansen JT.  Netter's Clinical Anatomy. Copyright © 2014, Copyright © 2014 by Saunders, an imprint of Elsevier Inc.

Open Access  This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made. The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

3

Laboratory Interpretation of Rheumatic Diseases Altaf Abdulkhaliq and Manal Alotaibi

3.1

Introduction

disease via the association of ankylosing spondylitis (AS) with HLA-B27 and RA with certain Generally the diagnosis of rheumatic diseases is HLA-DR alleles [4, 5]. based on a set of clinical, serological, and radioHence the salient existence of such immulogical measures. The discovery of a novel test nologic laboratory tests has assisted the more that appears to be considerably more disease-­ precise diagnosis of diverse rheumatologic condispecific and preferably sensitive would be of tions that may share some clinical characteristics. value for the early diagnosis and immediate, In addition, these tests can provide valuable evieffective therapy to prevent joint deterioration, dence concerning disease manifestation, activity functional disability, and unfavorable disease and prognosis, and therapeutic monitoring. outcome [1]. Essential terms concerning the laboratory tests However, components of acute phase reac- are needed to be defined such as sensitivity, specition proteins such as erythrocyte sedimenta- ficity, and positive and negative predictive values. tion rate (ESR) and C-reactive protein (CRP) Sensitivity refers to the ability of the test to detect or rheumatoid factor (RF) lack specificity and the proportion of patients with a disease which sensitivity and could not reach the expectation usually have a positive test result. However, speciof earlier diagnosis of specific rheumatic dis- ficity refers to the ability of the test to detect the eases. Therefore, the discovery of immunologic proportion of patients without the disease which laboratory tests has occupied a valued position usually have a negative test result. Predictive in the practice of rheumatology and has helped value refers to the likelihood of disease or nondefine the pathophysiology of various rheu- disease based on a positive or negative test result. matic conditions such as the immunologic basis A high positive predictive value test indicates that of rheumatoid arthritis (RA) [2, 3] and explain the patient with a positive test result most probthe contribution of genetic basis to autoimmune ably has the disease in question. Similarly, a high negative predictive value test indicates that the patient with a negative test result most likely does A. Abdulkhaliq (*) not have the disease in question. College of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia Unlike with sensitivity and specificity of the test, e-mail: [email protected] the predictive value is markedly affected by disease M. Alotaibi prevalence. For instance, the predictive value of a Northwestern University Feinberg School of positive rheumatologic test in patients with polyMedicine, Chicago, IL, USA arthralgia is likely to be higher in a rheumatology Internal Medicine Department, College of Medicine, clinic than in a family physician’s clinic [6]. Umm Al-Qura University, Makkah, Saudi Arabia

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The subsequent sections will discuss the stepwise approach to the diagnostic workup of rheumatic diseases and are presented as follows: • Inflammatory markers (ESR and CRP) • Rheumatoid factor (RF) • Antinuclear antibody (ANA) profile, for instance, anti-double-stranded DNA antibodies (anti-dsDNA) and anti-ribonucleic protein (RNP) antibodies • Other disease-specific antinuclear antibodies and cytoplasmic antibodies • Complement deficiencies and decreased complement activity in certain medical conditions • Components and classification of synovial fluid analysis • Other biochemical tests: renal function tests and urine analysis (this section is not in the scope of the current chapter but it will be discussed in details in the chapter of “Renal System and Rheumatology”)

3.1.1 Objectives By the end of the current chapter, the candidates should be able to: • Identify the rule of acute phase reaction proteins in rheumatic diseases. • Interpret the auto-antibodies’ results based on clinical findings. • Classify various types of joint effusions based on clinical and laboratory analysis of synovial fluid.

3.2

Acute Phase Reactants

Acute phase reactants (APRs) or proteins are defined as those proteins whose serum concentrations increase or decrease by at least 25% during inflammatory states. Changes in levels of APR largely result from the effects of cytokines, including interleukin (IL)-6, IL-1 beta, tumor necrosis factor-alpha (TNF-alpha), and interferon gamma.

Serum APR level measurements are useful because they frequently reflect the presence and intensity of an inflammatory process. The ­assessment of APR may be most helpful in patients with RA, polymyalgia rheumatica, and giant cell arteritis. However, APR measurements in clinical use are not specific to any particular disease. The most widely used indicators of the acute phase response are the ESR and CRP [7]. ESR and CRP definitions, measurements, uses, and other important aspects are addressed in Table 3.1.

3.3

 heumatoid Factor (RF) and R Anti-citrullinated Protein Antibody (ACPA)

3.3.1 Definition RF is an antibody directed against the Fc fragment of immunoglobulin G (IgG). It may be of any isotype: IgG, IgA, IgE, and IgM.  RF-IgM is the only one measured in clinical practice. The origin of RF is incompletely understood [7]. ACPAs are antibodies that are targeted against citrulline which is situated on proteins. Important clinical features of RF including measurement and common issues while dealing with it in clinical practice are all addressed in Table 3.2.

3.4

Antinuclear Antibodies (ANAs)

3.4.1 Definition ANAs are serologic hallmarks of patients with systemic autoimmune disease. These antibodies should be ordered when the clinical assessment of the patient suggests the presence of an autoimmune or connective tissue diseases [7]. Clinical aspects of ANAs are discussed in Table 3.3.

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Table 3.1  ESR versus CRP Definition

ESR ESR is an indirect measurement of serum acute phase protein concentrations, defined as the rate (mm/hour) at which erythrocytes suspended in plasma settle when placed in a vertical tube, reflects a variety of factors, most notably the plasma concentration of fibrinogen [7]

Methods of measurement

Cont. ESR The Westergren method The Wintrobe method Uses a 100-mm tube and has Uses a 200-mm tube and has a dilution step that correct for the effect no dilution step [7, 8] of anemia. It is the preferred method and can detect an ESR more than 50–60 mm/h [7, 8] An advanced rate does not diagnose a specific disease, but it does indicate that an underlying disease may exist [7, 8]

Sensitivity and specificity

Normal result

CRP CRP is defined as a pentameric protein comprised of five identical, non-covalently linked 23-KD subunits arranged in cyclic symmetry in a single plane. It is a component of the innate immune response and has both pro-inflammatory and anti-inflammatory actions. CRP can activate the complement system and enhance the apoptotic cell clearance [7] Cont. CRP It is measured by immunoassay technique or nephelometry [7]

Although CRP is a sensitive reflector of inflammation, it is not specific for inflammation [9] An elevated ESR observed together with a normal CRP is often a false-positive value for the ESR; this may reflect the effects of blood constituents, such as monoclonal immunoglobulins, that are not related to inflammation but that can influence the ESR. However, this conclusion is not always valid. As an example, the ESR may be markedly elevated in patients with active systemic lupus erythematosus (SLE), while the CRP response is muted. These variations may be explained by differences in the production of specific cytokines or their modulators in different diseases [10] – Normal value is less than 0.08 mg/dl – Normal values for the Westergren – CRP levels vary with age, sex, and race [7] method are: – The age-adjusted upper limit of normal for CRP is: Men = 0–15 mm/h Male = age in years/50 Women = 0–20 mm/h Female = (age in years/50) + 0.6 [9] Children = 0–10 mm/h – A normal value does not rule out the disease – Non-inflammatory conditions that can elevate ESR include aging, female sex, obesity, pregnancy, and race [7, 8] – The age-adjusted upper limit of normal for ESR is: Male = age/2 Female = (age+10)/2 (continued)

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Table 3.1 (continued) Abnormal results

Advantages and disadvantages

1-Causes of marked ESR elevation (more than 100 mm/hr): 1. Infection (bacterial 33%) 2. Connective tissue diseases (gain cell arteritis, polymyalgia rheumatica, SLE, vasculitides 25%) 3. Malignant neoplasms and renal disease 17% 4. Inflammatory disorders 14% [7, 11] Causes of marked decreased in ESR (0 mm/h): 1. Afibrinogenemia/ dysfibrinogenemia 2. Agammaglobulinemia 3. Increased plasma viscosity 4. Extreme polycythemia [7, 11] 1. Inexpensive, familiar, and easy to perform 2. As a patient’s condition worsens or improves, the ESR changes are relatively slow [12] 3. A literature review was conducted for all clinical trials and observational studies of diseasemodifying medications and corticosteroids in RA to elaborate on the laboratory results of both ESR and CRP before treatment and 4 weeks to 24 weeks after treatment in the same patients, and it has been concluded that the ESR was more sensitive to change than the CRP at 12 weeks and 24 weeks of treatment [13]

Values between 0.3 and 1 mg/dL may indicate: 1. Minor degrees of inflammation, e.g., periodontitis 2. Minor degrees of metabolic malfunction (non-­ inflammatory states), e.g., obesity and insulin resistance [7, 9] Values greater than 1 mg/dL can indicate: Clinically significant inflammation [9] Values greater than 8–10 mg/dL may indicate:   1. Bacterial infection   2. Systemic vasculitis   3. Metastatic cancer   4. Trauma, burns, and surgery [7, 9]

1. It rises more quickly and falls more quickly than ESR [11] 2. Measurements of CRP concentrations are of prognostic value in rheumatoid arthritis and can help guide management [11, 13–15] 3. CRP alone may have been in favor as a simple, validated, reproducible, non-age-dependent test for disease activity assessment [12] 4. CRP had been found to be more sensitive and specific marker for diagnosing bacterial infections in SLE compared to procalcitonin (PCT) [14, 15]. However, further meta-analysis report of studies describing the role of PCT or CRP as a biomarker of infection in autoimmune diseases has determined that PCT test is more specific than sensitive [16]. In addition, a later study has confirmed that PCT test is superior to CRP test in detecting superimposed bacterial infections in active SLE patients, where the PCT levels are correlated with the progression of bacterial infection and used to monitor the response to antibiotic treatment [17] The serum protein electrophoresis is the most sensitive test for detecting inflammatory changes. It is the most expensive, directly quantifies the acute phase response [7]. However, there is no single best laboratory test to reflect inflammation The optimal use of acute phase protein measurements may be to obtain several measurements, most commonly ESR and CRP, rather than a single test [9, 14, 18] Additional tests suggest systemic inflammation: Low albumin and mild elevation of hepatic alkaline phosphatase [7]

3.4.2 Methods of Measurement • Indirect immunofluorescence method using “fluorescence microscope” is the gold standard method to detect ANAs. Currently most laboratories use human epithelial cell tumor line (HEp2 cells) as a substrate to detect anti-

bodies that bind to various nuclear antigens (ANAs) instead of frozen section of rodent organ cells. • Other methods that can be used for detection of specific ANA include ELISA, immuno-­b lotting, and Western-blotting methods.

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Table 3.2  Characteristics of RF Measurement

Sensitivity and specificity

Positive results Cont. Positive results

Can RF be used as a screening test?

It is measured by nephelometry, radioimmunoassay, enzyme-linked immunosorbent assay (ELISA), and latex agglutination techniques, although there is no single technique that has clear advantage over others. Automated methods, such as nephelometry and ELISA, tend to be more reproducible than manual methods [7]. The most commonly used technique to measure ACPA is the ELISA for antibodies against cyclic citrullinated peptides (CCP). • The sensitivity of RF in RA has ranged from 26% to 90% • The reported sensitivity of the RF test in RA has been as high as 90%. However, population-­ based studies, which include patients with mild disease, have found much lower rates of RF-positive RA (26 to 60%) [19] • The sensitivity of ACPA testing is similar to RF at around 75%. However it provides much higher specificity rates at around 95%. • The specificity is 85% [19] • The specificity to a young healthy population is about 96% [19, 23] The common denominator for the production of RF (positive result) is chronic immune stimulation Healthy individuals Non-rheumatic disorders Rheumatic disorders 1. Rheumatoid arthritis   • RF is present in some healthy 1. Chronic infection, e.g., 26–90% AIDS, mononucleosis, individuals, especially the 2. Sjögren’s syndrome parasitic infections, chronic elderly (3–25%), male and 75–95% viral infection (hepatitis B or female are affected equally, hepatitis C (HCV) 54–76%), 3. Mixed connective and only 20% of cases is the tissue disease 50–60% chronic bacterial infections RF level significantly 4. Mixed (tuberculosis, subacute positive cryoglobulinemia bacterial endocarditis (SBE))   • RF has been found in 2–4% (types II and III) of young, healthy individuals 2. Cryoglobulinemia 40–100% 40–100% especially with HCV [7, 20] 5. Systemic lupus 3. Pulmonary disorders, such erythematosus as sarcoidosis 15–35% 4. Malignancy, especially after 6. Polymyositis or radiation or chemotherapy dermatomyositis and B-cell neoplasms 5–10% 5. Primary biliary cirrhosis 7. Sarcoidosis 15% [7, [7, 21] 21] Positive ACPA can be found in ACPAs were found to be the following non positive in the following rheumatological diseases: 1. Active tuberculosis (varying autoimmune diseases: 1. SLE and primary rates) Sjogrens Syndrome 2. Chronic obstructive (17%) pulmonary disease (5%) 2. Psoriatic arthritis 3. It is important to note that (8-16%) unlike RF, ACPAs are rarely found in patient with hepatitis C virus • Measurement of RF is a poor screening test to diagnose or exclude rheumatic disease in either healthy populations or in those with arthralgias but have no other symptoms or signs of rheumatic disease [20] • In a population study, it has been found that the presence of both RF and anti-citrullinated protein antibody (ACPA) in apparently healthy people substantially increases the probability of having RA. So the presence of the two autoantibodies (RF and ACPA) is associated with a relative risk of approximately 70% [20] • The RF has a higher positive predictive value (PPV) if ordered more selectively in patients with a modest or higher chance of having an RF-associated rheumatic disease such as RA, Sjögren’s syndrome, or the mixed cryoglobulinemia syndrome. Included in this group are patients with prominent morning stiffness, with sicca symptoms, or with arthralgia or arthritis in a rheumatoid distribution (i.e., symmetric polyarthritis involving small joints) [19] • Higher titers of RF have a higher positive predictive value for RA [19]. (continued)

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Table 3.2 (continued) Significance of measuring RF and ACPA in known RA cases

RF and monitoring of rheumatic diseases

Antibody status (ACPA/RF)

RF and the mortality

• RF-positive patients with RA may experience more aggressive and erosive joint disease and extra-articular manifestations than those who are RF-negative. Similar findings have been observed in juvenile idiopathic arthritis [19] • RF status may be useful in combination with other indicators, including HLA-DRB1, CRP, the ESR, and severity of synovitis on physical exam, to predict progression of radiographic changes in RA patients and to guide treatment [19] • ACPA positivity was found to be associated with more erosive joint disease, especially apparent on radiographs. It was also found to be better at predicting these changes than RF • The change in RF level does not reflect changes in RA disease activity • RF should not be used routinely to monitor RA disease activity in clinical practice • RF titer may fall with effective treatment of RA in patients who are originally RF-positive [19, 22] • In Sjögren’s syndrome, the disappearance of a previously positive RF may herald the onset of lymphoma. That is why some clinicians check RF repeatedly in patients with Sjögren’s syndrome. The clinical utility of this practice, however, has not been critically assessed [19, 22] • RF and ACPA have the potential to revert and convert during the early course of disease. Fluctuations in RF and ACPA were not associated with clinical outcomes [23] • Repeated measurement of ACPA or RF during the first year after onset of arthritis does not offer major additional information [24] Patients with RA with positive RF, especially IgA and IgM isotypes, carry a risk of dying earlier than patients without these serological findings [25]

Table 3.3  ANA characteristics Positive result

Is ANA used as a screening test?

• It is defined as the level of ANA that exceeds the level seen in 95% of the normal population • In most laboratories, this level is a titer of 1:40 to 1:80 that are reported positive • Clinically significant titers in laboratories that use HEp-2 cells as substrate are usually more than or equal to 1:160 [7, 26] Systemic autoimmune Organ-specific autoimmune diseases Infections Others diseases 1. Hashimoto’s thyroiditis 46% – Chronic infectious 1. Highly relatives of   1. SLE 93% patient 15–25% 2. Graves’ disease 50% diseases   2. Scleroderma 85% 2. Normal elderly 3. Autoimmune hepatitis 63–91% (mononucleosis,   3. Mixed connective 20% 4. Primary biliary cirrhosis 10–40% hepatitis C tissue disease 93% 3. Patients with 5. Primary autoimmune cholangitis infection, SBE,   4. Polymyositis/ silicone breast 100% tuberculosis, and dermatomyositis implant 15–25% HIV) and some 6. Idiopathic pulmonary arterial 61% [7] hypertension 40% lympho-­   5. Rheumatoid arthritis 7. Multiple sclerosis 25% [7, 26] proliferative 41% diseases   6. Rheumatoid – Malignancy (rare) vasculitis 33% with the exception   7. Sjögren’s syndrome of dermatomyositis 48%   8. Drug-induced lupus [7, 26] 95–100%; (e.g., procainamide, hydralazine, isoniazid, and quinidine)   9. Discoid lupus 15%   10. Pauci-articular juvenile chronic arthritis 71% [7, 26] – No, it cannot be used as a screening test for autoimmune disorders in the general healthy population in the absence of clinical findings as it may be present in very low specificity titer in normal population 5% – It should be used primarily as a confirmatory test when the clinicians strongly suspect SLE or autoimmune disorders – A patient with a negative ANA and strong clinical evidence of SLE or another SS-A-associated disease, antibodies to SS-A should be ordered [7]

(continued)

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Table 3.2 (continued) Is ANA used for monitoring diseases? ANA patterns

ANA titer

3.5

– No, there is no evidence about use of ANA titer as a monitor to follow disease activity in patients with SLE and autoimmune diseases [7]

The pattern type has been found to have relatively low sensitivity and specificity for different autoimmune disorders, and thus tests for specific antibodies have largely replaced the use of patterns The centromeric The homogeneous or The peripheral or The speckled The nucleolar pattern diffuse pattern rim pattern pattern pattern It is produced by Represents antibodies to It is produced by It is produced by It is produced by antibodies to RNA antibodies to proteins the DNA-histone antibodies to DNA antibodies to polymerase I, that are associated complex (anti-DNP (LE (anti-dsDNA) and SM, RNP, Ro/ proteins of the small with the site of cell) and anti-histone) antibodies to SSA, La/SSB, nucleolar RNP chromosomal nuclear envelope Scl-70, complex (fibrillarin, constriction. Proteins antigens centromere, designated, CENP-A, (anti-laminin) proliferating cell Mpp10, and hU3–55 K), Th/to, CENP-B, CENP-C, nuclear antigen etc., are only present B23, PM-Scl, and (PCNA), and on active centromeres NOR-90, and other other antigens (i.e., during meiosis antigens and mitosis) [7, 26] – The presence of very high concentrations of antibody (titer >1:640) should arouse suspicion of an autoimmune disorder. However, its presence alone is not diagnostic of disease – If no initial diagnosis can be made, it is our practice to watch the patient carefully over time and to exclude ANA-associated diseases – An accurate ANA with titer, in combination with a full history and physical examination, can be extremely useful in the diagnosis and exclusion of connective tissue disease [26] – 1–2% of patients who have active and untreated SLE will have a negative ANA, and this is because the substrate used in ANA test did not contain a sufficient antigen to detect SS-A antibodies – 10–15% of SLE patients will become ANA-negative with treatment or inactive disease – 40–50% of SLE patients with end-stage renal disease on dialysis will become an ANA-negative [7]

ANA Profile

3.5.1 Definition An ANA profile consists of many antibodies to measure specific ANAs for certain nuclear antigens. It should be performed when the screening test for ANA is positive and when further information is needed regarding the type of autoimmune disorder [7]. ANA profile antibodies and their specific uses are elaborated on Table 3.4.

3.6

Other Disease-Specific Antinuclear Antibodies and Cytoplasmic Antibodies

These antibodies have to be ordered individually according to the set-up diagnosis based on patient’s symptoms and clinical presentations, and they include:

1. Anti-histone antibodies: sensitive (70%) for drug-induced lupus but nonspecific and have limited diagnostic utility because they may also be present in patients with SLE. The best test to conduct in patient with suspected drug-­ induced lupus is antichromatin antibody test, not anti-histone antibody test [7]. However, anti-histone antibody test might be of value in patients having a positive ANA test with history of exposure to medications-induced lupus, such as procainamide (Pronestyl) and isoniazid (INH) [27]. 2. Anti-Th/To antibodies: crest syndrome 20% [7]. 3. Anti-SCL-70 antibodies (topoisomerase1): diffuse systemic sclerosis (scleroderma) 22–40% [7]. They are highly specific but not sensitive for scleroderma [29]. 4. Anti-tRNA synthetase antibodies (anti-­ Jo-­1, other): polymyositis 20–30% [7]. 5. Anti-neutrophil cytoplasmic antibodies (ANCAs):

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Table 3.4  The standard ANA profile Measured antibodies Anti-dsDNA antibodies (directed against double-­ stranded DNA)

Associated diseases SLE 60%

Anti-U1 RNP antibodies (ribonuclear protein)

SLE 30%, progressive systemic sclerosis (low titer), and mixed connective tissue disease (MCTD) SLE 30%

Anti-SM (smith) antibodies

Anti-SS-A (RO) antibodies

SLE 30%, primary Sjögren’s syndrome 70%, neonatal lupus, sub-acute cutaneous lupus (SCLE), secondary Sjögren’s syndrome (rare) [28]

Characteristics – It is very specific for SLE – It is the one that used to follow SLE disease activity; high titers are associated with lupus nephritis or a flare of lupus activity [27] – A very high level of this antibody is highly suggestive of MCTD [28]

– It is very specific for SLE – The sensitivity of anti-dsDNA and anti-Sm for the diagnosis of SLE is relatively low – Anti-Sm antibodies generally remain positive, even when a patient has entered remission; therefore it may be especially useful diagnostically when a SLE patient’s disease is relatively inactive [28]

Table 3.4 (continued) Measured antibodies Anti-SS-B (LA) antibodies Anti-­ centromere antibodies

Associated diseases SLE 15%, Sjögren’s syndrome 60% [28] Crest syndrome 98%, diffuse scleroderma 22–36% [28]

Characteristics

• Cytoplasmic anti-neutrophil cytoplasmic antibodies (C-ANCA), the most common c-ANCA target is serine proteinase-­3: granulomatous polyangiitis (GPA) (Wegener granulomatosis) 90%, microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA) (rare). Its titer can correlate with GPA disease activity [30]. • Perinuclear anti-neutrophil cytoplasmic antibodies (P-ANCA), the most common p-ANCA target is myeloperoxidase: MPA 70%, pauci-immune glomerulonephritis, and EGPA, or myeloperoxidase (−)— ulcerative colitis, chronic infection, and neoplasm (rare) [30]. 6. Anti-mitochondrial antibodies (AMAs): primary biliary cirrhosis 80% [7]. 7. Antibodies to the gp210 and p62 proteins of the nuclear pore complex: primary biliary cirrhosis 10–40% [7].

3.7

Circulatory Complement Components

Complement is an important effector pathway of innate immunity and has a role in the pathogenesis of some of rheumatic conditions, namely, SLE. Causes of Decreased Circulatory Complement Components • Hereditary complement deficiencies (decreased production) • Secondary complement deficiencies (acquired) [31]

3  Laboratory Interpretation of Rheumatic Diseases

3.7.1 Mechanism of Acquired Complement Deficiencies 1. Increased level of circulatory immune complexes (increased consumption of complements) due to: • Infectious causes • Glomerulonephritis • Rheumatic diseases: (a) SLE: Low C4 and C3 levels occur in about 50% of patients with SLE. Levels of C3 and C4 are decreased with increased severity of SLE, especially renal disease. A return to normal levels with treatment is a good prognostic sign. Serial observations reveal decreased levels preceding clinical exacerbation. (b) Cryoglobulinemia: The complement profile shows decreased levels of C4 and C2 with normal or slightly lowered C3. (c) Systemic vasculitis especially polyarteritis nodosa, urticarial vasculitis: 50% of patients with polyarteritis may have decreased serum complement levels. Its values can be helpful in assessing the clinical course, especially the response to therapy. (d) RA with extra-articular manifestation (rare) [7, 32]. 2. Reduced hepatic synthesis (uncommon) 3. Loss of complement components in the urine (rare) [30]

3.8

Synovial Fluid Analysis

The presentation of one or more hot, swollen joints is a common medical emergency, and synovial fluid aspiration, the so-called arthrocentesis, is the single most important test helping in the diagnosis of different types of arthropathies [33]. Therefore, specialized laboratories analyze synovial fluid to either confirm the diagnosis of crystal-associated arthropathies, support the diagnosis of septic arthritis, or establish other rheumatologic diagnoses such as mono-arthritis or joint effusion [34].

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The complete analysis of synovial fluid includes macroscopic (gross appearance), microscopic, and specific stain tests to provide detailed information about the joint’s condition and helps in establishing the diagnosis and treatment [35]. Description of macroscopic analysis of synovial fluid includes color, clearance, volume, and viscosity. However, the microscopic analysis can differentiate between inflammatory and infectious processes by measuring a complete leukocyte count. In addition, a differential of the synovial WBC count should be ordered, so that if the results came positive for infectious process, the performance of Gram-stain and culture tests will provide guidance to diagnosis and/or antibiotic therapy [36]. Microscopic examination specifically can also allow the detection and identification of various types of crystal by using polarized light microscope. Refer to Table 3.5 for an overview on important issues as regards arthrocentesis and synovial fluid analysis. However, Table 3.6 shows the classification of joint effusions into normal, inflammatory, non-inflammatory, and septic effusion based on clinical and laboratory analysis of synovial fluid with the causes of each type [37, 38]. Indications, contraindications, complications, and specimen analysis of synovial fluid are presented in Table  3.5. Classification and causes of joint effusions based on laboratory analysis of synovial fluid are presented in Table 3.6. Fig. 3.1 is the clinical diagnostic approach for painful peripheral joint.

3.9

Key Notes

• The likelihood diagnosis of septic arthritis is markedly increased with higher synovial WBC counts. It has been illustrated that for synovial WBC count the likelihood ratio (LR) of having septic arthritis is as follows [34]: –– WBC count 50,000/μL, the LR is 7.7 at 95% CI.

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Table 3.5  Overview on arthrocentesis and synovial fluid analysis Indications   1. According to the American College of Rheumatology (ACR), synovial fluid analysis should be performed in the febrile patient with an acute flare of established arthritis to rule out superimposed septic arthritis   2. Unexplained joint, bursa, or tendon sheath swelling   3. Suspected crystal-­ induced arthritis   4. Repeated aspiration and analysis may be indicated to follow up the response of septic arthritis to treatment and may also be valuable for diagnosis of some cases of gout in which the initial aspirate does not have detectable crystals [34]

Contraindications 1. There is no absolute contraindication 2. Bleeding diatheses and cellulites are considered as relative contraindication; it could make the approach to the joint space difficult due to the overlying swelling [37]

Complications 1. Infection 2. Hemarthrosis 3. Pain 4. Cartilage injury 5. Vasovagal syncope [37]

Specimen handling 1. Aspiration is performed under aseptic technique with quick transfer of specimen for culture to the sterile tubes and plated as soon as possible 2. If the transfer is delayed more than 6 hours, many changes would occur, for example, decrease in leukocyte count or decrease in crystal numbers [36]

Synovial fluid analysis The WBC count and the percentage of PMN cells can help to differentiate between non-­ inflammatory, inflammatory, and septic joint conditions. These tests are the best diagnostic tool available for detecting bacterial arthritis [36] 1. Gram stain and cultures should be ordered even with relatively low suspicion of infection 2. Crystal search using polarized light microscopy 3. Chemistry analysis should not be routinely ordered [37]

Table 3.6  Classification and causes of joint effusions based on laboratory analysis of synovial fluid Fluid features Appearance

Total WBC count/ MM3 Polymorphonuclear cell (PMN)% Causes

Normal Clear, highly viscous, colorless 0–200

Non-inflammatory Clear to slightly turbid

Inflammatory Slightly turbid, yellow or yellow-green

Pyarthrosis or septic arthrosis Turbid to very turbid, yellow or yellow-green

200–2000

2000–50,000

50,000–150,000

0.409 mcg/mL (0.9 μM); increase leucovorin dosage immediately to 150 mg (approximately 100 mg/m2) IV every 3 h until methotrexate concentration declines to 3 times upper limit of normal or bilirubin is 3.1–5 mg/dL Renal impairment: CrCl10 mL/min, give full dose Can cause significant dose-related infertility in both men and women Nausea and vomiting, bone marrow suppression, alopecia, haemorrhagic cystitis and, rarely, bladder carcinoma

Adverse effects and caution Hyperglycaemia, hyperkalaemia, increased urea, hypertension, various infections, hypocalcaemia, hypercholesterolaemia and hypomagnesaemia Vomiting and diarrhoea are common Hepatic toxicities are infrequent but must be monitored

Pregnancy category: D Lactation: Excreted into breast milk, use not recommended

Pregnancy and lactation Pregnancy category: D Lactation: Excretion into breast milk is unknown, use not recommended

90 L. Borham and W. Hafiz

Inhibits the JAK-STAT signalling pathway

Small molecule inhibitor of PDE-4

Tofacitinib (Xeljanz)

Apremilast (Otezla)

Rheumatoid arthritis: 5 mg PO Q12hrs or 11 mg of the extended-release tablet daily Dosing modifications: Co-administration with cytochrome P450 3A4 inhibitors: Not to exceed 5 mg daily Moderate renal or hepatic impairment: Reduce dose to less than 5 mg daily It has not been studied in patients with severe haptic impairment or in patients with CrCl 3.0 or combined antiplatelet-anticoagulant (INR 2.0–3.0). There is no consensus agreement on this [5].

8.2.3 Seizure Seizure is a transient neurological dysfunction that results from excessive abnormal discharges of cortical neurons. Seizure can be generalized or focal in onset. The differential diagnosis of generalized-­onset seizure is different than focal-­ onset seizure (Table 8.4).

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A patient with a unilateral motor weakness and sensory symptom and loss of one of the higher cerebral functions like: aphasia Abbervation:-HgA1c:glycated haemoglobin, ECG:electrocardiogram Brain imaging to diagnose the cause of deficit Measure the blood sugar, HgA1c, lipid profile to assess cardiovascular risk factors. ECG, Holter moniter, Echocardiogram and carotid Doppler Antiphospholipid antibodies

Rule other causes of stroke in young:1- Inherited hypercoagulable state 2- Drug abuse 3- Mitochondrial disaeses

1. Use thrombolytics within the appropriate time frame unless contraindicated. 2. Antiplatltes therapy 3. Risk factor modification 4. Anticoagulation for antiphospholipid antibodies

Fig. 8.3  Approach to SLE patients with acute stroke Table 8.4  Cause of generalized versus partial onset seizure Generalized seizure Electrolyte imbalance Medication side effect Uraemia Infection NPSLE

Partial-onset seizure Venous sinus thrombosis Posterior reversible encephalopathy Limbic encephalitis Infection Stroke

Different aetiological factors can cause seizure in SLE patients (Tables 8.5 and 8.6). The prognosis and the need for further treatment of seizure are dependent on the cause of seizure [6, 7].

8.2.3.1 Tips in History 1. Disease activities. 2. Seizure onset, duration, and postictal events. 3. Determine the seizure type by asking if there was a preceding aura and by taking exact description of seizure from a witness. 4. History of fever.

Table 8.5  Causes of seizure in SLE patients Electrolyte imbalance Uraemia Medication side effect Posterior reversible encephalopathy Infection (meningitis, encephalitis, cryptococcal meningitis) Limbic encephalitis Venous sinus thrombosis NPSLE (single unprovoked seizure) Table 8.6  workup of SLE patients present with single seizure Electrolytes Renal profile Liver profile CBC Brain MRI and MRV EEG

5. Any associated other neurological symptoms or signs. 6. Medication history. 7. History of comorbidities, e.g. hypertension or renal failure.

8  Nervous System and Rheumatology

8. Similar events in the past. 9. History of prior CNS insults, e.g. stroke. 10. Family history of epilepsy. Treatment with an antiepileptic is not indicated for a single unprovoked seizure and for seizure secondary to metabolic causes. Use an antiepileptic in the presence of recurrent events, abnormal EEG, and abnormal neuroimaging which carry a higher risk of recurrence without treatment. If seizure happens in a setting of high disease activities, treatment with immunosuppressive therapy is indicated.

8.2.4 Myelopathy It is a condition that results from inflammation of the spinal cord. Although it is considered rarer than other NPSLE syndromes, its development carries poor functional outcome. The classical presentation is with symptoms of spinal cord dysfunction including motor weakness, sensory loss with sensory level, and loss of sphincter control. The presentation differs according to the specific localization of the cord inflammation (Table 8.7). Patients with SLE can present with transverse myelitis and rarely can also present with longitudinal myelitis where more four segments of the cord are involved. The development of longitudinal myelitis carries a worse prognosis and mandates aggressive immunosuppressive therapy. In the presence of longitudinal myelitis, brain MRI Table 8.7  Symptoms and signs of myelopathy according to the spinal level Cervical cord

Thoracic cord

Motor weakness affecting four limbs (lower motor neuron signs at the level with upper motor neuron signs below the level of the lesion in chronic stage) Sensory loss below the level with cervical sensory level Loss of sphincter control Respiratory compromise in high cervical lesion Motor weakness below the lesion (usually upper limb preserved unless T1 involved) Sensory loss below the lesion with truncal sensory level Loss of sphincter control

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should be done to rule out brain demyelination. Anti-NMO antibodies (neuromyelitis optica) should be sent for those patients. When dealing with patients with symptoms of acute cord dysfunction, one should rule out surgical causes first as an early intervention will affect the outcome (Fig. 8.4). When surgical causes are excluded, patients should have CSF examination to rule out infectious causes of myelitis. Treatment with immunosuppressive therapy should be delayed. Combine it with antiviral therapy until negative culture is obtained. Different immunosuppressive regimens have been used in patients with myelopathy including pulse steroid therapy with or without intravenous cyclophosphamide or plasmapheresis. Aggressive therapy with combined three modalities can be used for patients with more severe disease especially with longitudinal myelitis, although one case series did not show superior outcome with the combined three modalities [8]. That observation may be explained by the fact that patients who had combined therapy had severe disease at their presentation. In a subgroup of patients with antiphospholipid antibodies, the use of anticoagulation is recommended.

8.3

Rheumatoid Arthritis

Rheumatoid arthritis (RA) is the most common inflammatory destructive joint disease. Besides its articular manifestations, patients with RA exhibit multiple extra-articular manifestations. The nervous system can be involved at varying degrees in patients with RA [9]. Both central and peripheral nervous system can be involved (Fig. 8.5). Central nervous system involvements can happen in the form of necrotizing vasculitis or as a result from cervical spine involvements and the development of atlantoaxial subluxation. Peripheral nervous system involvement can be primary due vasculitis or secondary to the joint deformities or compression from rheumatoid nodules. Also the nervous system can be involved secondary to drug side effect. The approach to patients with rheumatoid arthritis and atlantoaxial subluxation as well to patients presenting with neuropathy will be discussed (Fig. 8.6).

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Patient with feature of acute spinal cord dysfunction

Determine the exact level of the cord involved from history and examination

MRI of the cord

Feature of myelitis

Surgical cause is identified

Neurosurgical referral

Check disease activity CSF examination including viral serology and cultures

Start immunosuppressive therapy Plus antiviral pending the CSF results

Fig. 8.4  Approach to patient with suspected myelopathy Fig. 8.5  Causes of neurological manifestations of RA

Causes of neurological manifestations of RA:

By the dense.

Compression of nervous tissue.

Necrotizing vasculitis.

By inflamed adjecent structures like: tendons.

By rheumatoid nodules.

Treatment side effects.

8  Nervous System and Rheumatology

• High Rheumatoid factor titres. • Other extra -articular manifestations of RA beside the neurological ones. • Presence of erosive joints disease on radiograph or long disease duration. RA with.

History and physical examination.

• History of neck pain radiaitng to the occipt. • History of motor weakness and parasthesia of the hands and the feet. • Ask about history of trauma. • Think of possible medications side effects. • Do a complete neurological examination to confirm the presence of atlantoaxial sublaxation.

• Order RF, CRP, ESR, WBC. • Order x-ray of the peripheral joint looking for erosion. • Order MRI of the spine to confirm the diagnosis after stablizing the patient if the compression is acute. Investigations.

• Glucocorticoid in the case of acute compression. • Surgical treatment is the definitive treatment of this condition (decompression and fusion). • Get RA under control Treatment.

Fig. 8.6  Approach to RA patient with suspected atlantoaxial subluxation

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8.3.1 Atlantoaxial Subluxation 1. RA is the most common inflammatory disorder affecting the cervical spine. The involvement of cervical spine is related to active erosive RA and early age of onset [10]. 2. Craniocervical complications arise in 30–50% of patients with RA more than 7  years; however, the atlantoaxial subluxation with myelopathy develops in 2.5% of RA more than 14 years [11]. 3. Cervical spine involvements by RA include atlantoaxial subluxation, cranial settling, subaxial subluxation, or combinations of the above. 4. Atlantoaxial subluxation is the most common type of cervical spine affection. 5. The subluxation can be anterior, posterior, or lateral, and the anterior subluxation is the most common type that results from laxity of the primary and secondary ligamentous structures. 6. It is very important to recognize this particular complication especially in neurologically normal patients, as early recognition and treatment will improve outcome. 7. Patients with atlantoaxial subluxation can be asymptomatic, or more commonly involve complaints of neck pain. Patients may present with occipital neuralgia, facial pain, ear pain, or pain in the suboccipital region. 8. In cases where cord compression already developed, patients would present with weakness, sensory symptoms related to the cord compression, as well as loss of sphincter control. (When you deal with any RA patients presenting with any of the above symptoms, consider atlantoaxial subluxation). 9. Detailed neurological examination is mandatory with careful evaluation for signs of myelopathy. 10. In order to prevent the development of neurological sequels, an evaluation for possible atlantoaxial subluxation radiologically is mandatory for any patient with RA at presen-

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tation and periodically thereafter and prior to any surgical procedures. 11. If atlantoaxial subluxation is suspected, besides assessing the disease activity with DAS-28 score, for example (see Chap. 1), and peripheral joint X-ray, the status of the cervical spine should be assessed. Plain X-ray that includes lateral, anteroposterior, open mouth odontoid views and lateral flexion-­extension dynamics is necessary to assess joint stability. More advanced imaging is required for patients with neurological symptoms to assess multilevel disease. MRI is better than CT scan to evaluate the neurological structures as well as to provide better look at the ligamentous structures. The mainstay of treatment is early surgical intervention before the onset of severe neurological dysfunction, appropriate and aggressive disease-­modifying therapy to control the disease activity, and adequate rehabilitation services to optimize neurological outcome.

8.3.2 Neuropathy Neuropathy in patients with RA can result from nerve compression or secondary to vasculitis. When RA patients present with symptoms of mononeuropathy, it is essential to differentiate between neuropathy related to nerve compression and vasculitis as the treatment will be different. Take appropriate history related to neurological complaints. The onset of symptoms, progression, and whether there is sensory and/or motor deficits should be checked. Check if the symptoms are all related to one nerve or multiple nerves (mononeuritis multiplex). Assess RA activity, severity with the presence of erosions on X-rays, functional decline, duration, and medications used for RA. On examination, try to identify the deficit and if you can which nerve is involved (Table  8.8). Examine all other peripheral nerves to assess whether it is a single or multiple processes. Examine the activity of RA and

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Table 8.8  Things to look for in common nerve involvements Nerve Radial nerve

Median nerve

Ulnar nerve

Femoral nerve Sciatic nerve

Common peroneal nerve

Motor symptoms Wrist drop due to weakness of extensors of the wrist and the fingers. Loss of elbow extension if the upper third of the nerve is affected Loss or weakness of the thumb abduction mainly Loss of wrist flexors

Weakness of most of the small muscles of the hand which will lead clawing of the hand Weakness in knee extension Weakness of all the muscles below the knee that results mainly in foot drop and weakness of the hip flexion Foot drop

Sensory symptoms Loss of sensation over the anatomical snuff box

Notes Flex the elbow, pronate the forearm, and extend the wrist and the fingers to demonstrate wrist drop if it is not clear

Loss of sensation over the palmer aspect of the thumb, index, middle, and lateral half of the little finger and the corresponding part of the palm if it is affected above the wrist Loss of sensation over the little finger the medial half of the ring finger

Pen touching test for lesion at the wrist. Ochsner clasping for lesion in the cubital fossa Froment’s test can be used to demonstrate loss of thumb adduction in ulnar nerve affection

Loss of sensation over the medial aspect of the thigh and the leg Loss of sensation over the posterior aspect of the thigh, all the aspects of the lower limb below the knee except for the medial aspect of the leg

It divides into the common peroneal nerve and the posterior tibial nerve at the level of the knee

Usually minimal sensory loss over the lateral aspect of the dorsum of the foot

Loss of eversion is another feature

assess deformity. Look for rheumatoid nodules. Nerve conduction studies (NCS) and electromyogram (EMG) will help to establish the diagnosis of nerve involvements. If it develops in a site of entrapment, e.g. carpal tunnel for median nerve and tarsal tunnel for posterior tibial nerve, the condition is most likely to be related to nerve compression rather than vasculitis and requires supportive care and may require surgical intervention. Neuropathy that develops in a non-­ compression site is related to vasculitis. Those patients may exhibit mononeuropathy or features of multiple nerve involvement (mononeuritis multiplex). Usually it happens in the setting of active erosive disease and with seropositive disease. Treatment with steroid should be initiated together with the use of disease-modifying therapy to achieve disease control. Patients with RA can also present with features of peripheral neuropathy that can be sensory, sensory-motor, or motor neuropathy. The approach to such patients will be discussed in the next part.

8.4

Neuropathy with Skin Rash

When neuropathy either mononeuropathy, mononeuritis multiplex, or peripheral neuropathy occurs in a setting of skin rash, vasculitis should be considered as an etiological factor. Vasculitis is a condition that results from inflammation of the blood vessels. It can be primary or secondary to other conditions, e.g. connective tissue disease, infection (hepatitis C), hypersensitivity reaction, and paraneoplastic condition. (See Chap. 19 for full details about vasculitis.) Figure 8.7 shows the diagnostic approach to patient with neuropathy and rash.

8.4.1 T  ips in History and Physical Examinations 1. Identify the nature of neuropathy (sensory, sensory-motor, motor, mono, multiple versus peripheral).

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Palpable purpura which might be painful, motor weakness and sensory symptoms suggestive of neuropathy

Take full history and do appropriate and complete physical examination and order CBC, ESR, CRP, Rheumatology panel, biopsy, NCV, and EMG, renal and liver function tests, drugs screen, porphoria, vitamin assays and imaging modalities for suspected cancer.

History of liver disease and positive serology for Hepatitis B or C. Think of polyartritis nodosa, and cryoglobulinemia.

History of asthma, esinophilia with positive p ANCA think of eosinophilic granulomatosis with polyangiitis.

History of periorbital edema, urine changes, hypertension (renal involvement). - positive ANA, anti smith, anti DNA think of SLE. - Positive C ANCA think of microscopic poly angitis. - Gastrointestinal symptoms in patient less than 18 years old and history of preceding viral infection think of HSP

History of constitutional and site related symptoms with positive imaging think of para-neoplastic phenomenon.

History of either drug intake, or systemic viral infection think of hypersensitivity reactions (serum sickness).

In the case of primary vassculitis use glucocorticoids and cyclophosphamide. Control the precipitating condition in the case of secondary vassculitis in addition to same agents used for primary vassculitis e.g: DMARDS for connective tissue diseases antimicrobial for certain infection, discontinuation of the culprit drugs.

Fig. 8.7  Approach to patient with rash and neuropathy

2. Symptoms of asthma like shortness of breath 4. The age of the patient may give a clue since may suggest Churg-Strauss syndrome, eosinHSP is rare in a patient who is older than 18. ophilic granulomatosis with polyangiitis 5. Associated gastrointestinal symptoms are [EGPA], or allergic granulomatosis. important findings in HSP. 3. Symptoms of renal involvement like perior- 6. Symptoms of liver involvement are essential bital oedema and hypertension may suggest to be established as hepatitis C is associated ANCA-associated vasculitis including with cryoglobulinaemic vasculitis and hepamicroscopic polyangiitis and Henoch-­ titis B is strong risk factor for polyarteritis Schonlein purpura (HSP). nodosa.

8  Nervous System and Rheumatology

7. History of recent use of drugs or recent systemic viral infection that can be associated with hypersensitivity reactions. 8. Symptoms of connective tissue diseases like SLE, RA, and Sjogren disease are suggestive for a secondary cause of vasculitis. 9. Constitutional symptoms can be associated with rheumatologic diseases or solid tumours like lung cancer or lymphoma in what is known as paraneoplastic phenomenon. 10. Family history of similar presentation as some genetically determined disease, e.g. porphyria can present with skin rash and neuropathy. 11. High risk factors, e.g. multiple sexual partner and IV drug abusers, may suggest infections like HIV and/or syphilis. 12. The patient’s job is important to exclude exposure to certain toxins. 13. Pay attention to the patient’s nutritional status as vitamin deficiencies can lead to neuropathy and rash that might be mistaken for vasculitis. 14. Thorough systemic examination is mandatory to help narrow your differential diagnosis.

8.4.2 Laboratory Investigations and Imaging Modalities 1. CBC, C-reactive protein, and ESR to assess the presence of inflammatory condition in the body like vasculitis and connective tissue disease. 2. NCS and EMG help to categorize the type of neuropathy [12]. 3. Nerve biopsy is the ultimate gold standard to diagnose vasculitis as a cause of neuropathy [12]. 4. Rheumatologic autoantibody profile like ANA, ANCA, RF, anti-DNA, anti-RO, anti­Jo, and anti-CCP will help identify if vasculitis were secondary to connective tissue disease (see for details in Chap. 4). 5. Assess the patient’s liver, renal, thyroid, as well as glucose levels to help narrow the differential diagnosis.

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6. Serology for hepatitis B and C, HIV, and cryoglobulin level and VDRL to exclude secondary syphilis. 7. Vitamin assays like B12, folate, and E to exclude vitamin deficiency as the cause of patient presentation. 8. Toxicology screen looking for drug toxicities. 9. Look for porphyrins according to which subtype you suspect in the patient. 10. Use the different imaging modalities to look for solid tumour or lymphoma if you think they are the culprit.

8.4.3 Treatment 1. Immunosuppressive therapy with glucocorticoids is the mainstay of treatment. Depending on disease severity, the addition of cyclophosphamide should be considered to minimize the risk of relapse, morbidity, and mortality [13]. 2. Control the precipitating condition in the case of secondary vasculitis in addition to same agents used for primary vasculitis, e.g. DMARDs for connective tissue diseases, antimicrobial for certain infection, discontinuation of the culprit drugs, etc. Acknowledgments The Authors would like to thank Fahd M. Almalki, MD, for his contributions to this chapter in the previous edition. The authors also would like to thank Dr. Waleed Hafiz for his assistance in the development of this chapter.

References 1. Hanly JG, Urowitz MB, Su L, Bae SC, Gordon C, Wallace DJ, et  al. Prospective analysis of neuropsychiatric events in an international disease inception cohort of SLE patients. Ann Rheum Dis. 2010;69(3):529–35. 2. Ainiala H, Loukkola J, Peltola J, Korpela M, Hietaharju A. The prevalence of neuropsychiatric syndromes in systemic lupus erythematosus. Neurology. 2001;57(3):496–500. 3. Brey RL, Holliday SL, Saklad AR, Navarrete MG, Hermosillo-Romo D, Stallworth CL, et  al. Neuropsychiatric syndromes in lupus: preva-

190 lence using standardized definitions. Neurology. 2002;58(8):1214–20. 4. Joseph FG, Lammie GA, Scolding NJ. CNS lupus: a study of 41 patients. Neurology. 2007;69(7):644–54. 5. Ruiz-Irastroza G, Cuadrado MJ, Ruiz-Arruza I, Brey R, Crowther M, Dreksen R, et al. Evidencebased recommendations for the prevention and long term management of thrombosis in antiphospholipid antibody positive patients. Report of a task force at the 13th international congress on Antiphospholipid antibodies. Lupus. 2011;20(2):206–18. 6. Bertsias GK, Ioannidis JP, Aringer M, Bolen E, Bombardieri S, Bruce IN, et  al. EULAR recommendations for the management of systemic lupus erythematosus with neuropsychiatric manifestations: report of a task force of the EULAR standing committee for clinical affairs. Ann Rheum Dis. 2010;69(12):2074–82. 7. Alkhotani A.  Neuropsychiatric lupus. SQUMJ. 2013;13(1):19–23. 8. Kovacs B, Lafferty TL, Brent LH, DeHoratius RJ. Transverse myelopathy in systemic lupus erythe-

E. Alkohtani and A. Alkhotani matosus: an analysis of 14 cases and review of the literature. Ann Rheum Dis. 2000;59(2):120–4. Review 9. Sofat N, Malik O, Higgens CS. Neurological involvements in patients with rheumatic disease. QJM. 2006;99(2):69–79. 10. Ahn JK, Hwang JW, Lee J, Lee YS, Jeon CH, Cha HS, Koh EM.  Risk factors for development and progression of atlantoaxial subluxation in Korean patients with rheumatoid arthritis. Rheumatol Int. 2011;31(10):1363–8. 11. Wasserman BR, Moskovich R, Razi AE. Rheumatoid arthritis of the cervical spine clinical consideration. Bull NYU Hosp Jt Dis. 2011;69(2):136–48. 12. Seo JH, Ryan HF, Claussen GC, Thomas TD, OH SJ. Sensory neuropathy in vasculitis a clinical, pathologic, and electrophysiologic study. Neurology. 2004;63:874–8. 13. Mathew L, Talbot K, Love S, Puvanarajah S, Donaghy M. Treatment of vasculitic peripheral neuropathy: a retrospective analysis of outcome. QJM. 2007;100(1):41–51.

Open Access  This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made. The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

9

Diagnostic Approach to Proximal Myopathy Hani Almoallim, Hadiel Albar, and Fahtima Mehdawi

9.1

Introduction

Patients with muscle disorders are a diagnostic challenge to physicians, because of the various ways of presentation. A comprehensive approach should be followed systematically in order to reach the correct diagnosis. Weakness is a common symptom among patients including those with central or peripheral nervous systems diseases and those with muscular and/or neuromuscular diseases. Muscle weakness is not only a regular finding in rheumatologic diseases, but in inflammatory myopathies as well. This chapter focuses on skills needed to approach any patient that presents with weakness, specifically proximal myopathy. In addition to IIM and CTD, proximal myopathy has a wide range of differential diagnosis including drugs, alcohol, thyroid disease, hereditary myopathies, malignancy, and infections. Clinical assessment should aim to distinguish proximal myopathy from other conditions that present with weakness. Patients with proximal H. Almoallim Medical College, Umm Al-Qura University (UQU), Makkah, Saudi Arabia H. Albar King Faisal Specialist Hospital & Research Center, Jeddah, Saudi Arabia F. Mehdawi (*) Doctor Soliman Fakeeh Hospital, Jeddah, Saudi Arabia © The Author(s) 2021 H. Almoallim, M. Cheikh (eds.), Skills in Rheumatology, https://doi.org/10.1007/978-981-15-8323-0_9

myopathy who need prompt attention, like those with cardiac, respiratory, or pharyngeal muscle involvement, should be identified early and quickly. In this chapter, the aim is to provide a systematic diagnostic approach to adult patients presenting with proximal myopathy. This is an essential step to establish the correct diagnosis in order to conduct the appropriate management.

9.1.1 Objectives By the end of this chapter, you will be able to: 1. Identify true muscular weakness by history and physical examination. 2. Construct diagnostic approach to proximal myopathy. 3. Manage a case of inflammatory myopathy.

9.2

Clinical Presentation of Proximal Myopathy

Myopathies are diseases that primarily affect the muscles and are usually characterized clinically by weakness, fatigue, or stiffness. Symmetrical proximal muscle weakness, wasting, normal sensation, and normal stretch reflexes are classical findings in patients with myopathies particularly in IIM and myopathies associated with 191

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CTD.  Aching muscle cramps can also occur. Clinical presentations sometimes can be complex, hence the need to follow a comprehensive approach to weakness.

9.2.1 History Weakness is a common complaint with different interpretations by patients. The aim of history taking is to try to define what the patient means by “weakness.” The generalized feeling of tiredness and/or fatigability is usually associated with systemic diseases like congestive heart failure, cirrhosis, and anemia. In these patients there is usually a long-standing history of a chronic disease like ischemic heart disease and/or chronic liver disease. The activity in these patients is usually limited by dyspnea, chest pain, joint pain, fever, and/or depressed mood. Long-standing chronic diseases can lead to cachexia with severe muscle atrophy, wasting, and consequent generalized weakness. The sense of generalized tiredness and/or fatigability should be differentiated

from the complaints of generalized body aches and pains in patients with fibromyalgia. The generalized body aches and pains have their own approach that is beyond the scope of this chapter. Once it is established that the weakness is not a consequence of a non-muscular, generalized, systemic disease and there are no generalized body aches and pains, then it is essential to find out whether this weakness is localized to certain areas. Hemiparesis (weakness affecting upper and lower limbs on the same side of the body) should direct the history towards central nervous system diseases like stroke. Paraparesis (weakness of both lower limbs) and/or quadriparesis (weakness of the four body limbs) should limit the differential diagnosis to spinal cord and/or cerebral cortex and/or brain stem diseases. Monoparesis (weakness of one limb) is usually a disease of a peripheral nervous system including disc prolapse causing radiculopathy by compressing on a spinal nerve to peripheral nerve involvement in vasculitis. Figure  9.1 is a schematic that should be fol-

Fig. 9.1  The four anatomic stations underlying lower motor neuron weakness Sensory root

Motor root

Anterior horn cell (amyotrophic lateral sclerosis, spinal muscular atrophy, etc.)

Mixed nerve (contains motor and sensory fibers) (GuillainBarre syndrome, CIDP, etc.)

Sensory receptor

Neuromuscular junction (myasthenia gravis, botulinum, LEMS, etc.) Muscle (polymyositis, dermatomyositis, metabolic myopathies, etc.)

9  Diagnostic Approach to Proximal Myopathy

lowed while obtaining history and examining patients with weakness. Symmetrical weakness occurs in large number of diseases including inflammatory myositis, inherited muscle dystrophy, endocrine disorders, and neuromuscular junction diseases. In symmetrical and diffuse weakness, it is important to know if the weakness is proximal or distal. There are several clues in the history that point towards proximal myopathy (muscles of the trunk, shoulders, and thighs). The patient will have difficulty combing hair, difficulty climbing up the stairs, difficulty standing from a sitting position, and/or difficulty in getting up from bed. In distal myopathy, the patient will complain about difficulties while performing fine work like handling the objects by hands and driving. These patients may also present with wrist drop or foot drop. It must be noted that there are diseases affecting proximal muscles in an asymmetrical fashion like diabetic amyotrophy as well as diseases with both proximal and distal muscle weakness in symmetrical and/or asymmetrical fashion like in systemic lupus erythematosus (SLE) with myopathy and vasculitis, respectively. Inclusion body myositis, a rare IIM in elderly patients, presents with both proximal and distal myopathies simultaneously. The focus should be simply to identify the localization of the weakness, and then with comprehensive approach to history taking like what is described in Chap. 1, the differential diagnosis should be easier to obtain. There are special characters for weakness that signify certain alerts to specific diagnoses. Ascending pattern of weakness should direct the attention towards demyelinating diseases like acute inflammatory demyelinating polyneuropathy (Guillain-Barre syndrome). Descending patterns that start centrally and proceed progressively to distal areas should direct the attention to infections like botulism. The weakness that is worsened by repetitive movement at the end of the day with double vision and drooping eyelids should direct the attention towards neuromuscular disorders like myasthenia gravis. An extensive review of rheumatologic symptoms should follow; this was outlined thoroughly in Chap. 1. Detailed history of joint pain, skin rashes, fever, recent infections, bleeding tenden-

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cies, history suggestive of malignancies, and/or drug history (particularly statins and glucocorticoids) should all be obtained. Endocrine disorders should also be ruled out by reviewing common symptoms like neck swelling, diarrhea/ constipation, and heat/cold intolerance. Further details are found below. Detailed family history should be obtained as there are several rare hereditary myopathies that run in families (see below). A family history may also be present in other causes of weakness including dermatomyositis, polymyositis, and potassium-related paralyses. A thorough neurological history is important. Sensory deficits, impaired level of consciousness, speech or visual defect, seizure, and sphincter control should be obtained from patients with weakness. In addition, social history will further help narrow the diagnosis; thus, history of smoking, alcohol, illicit drug use, and exposure to toxins like organic phosphorus should be obtained. There are life-threatening symptoms associated with IIM like dysphagia and nasal regurgitation resulting from skeletal muscle involvement of the pharynx and upper third of the esophagus and/or chest pain and heart failure from cardiac muscle involvement. These should be identified promptly as they need urgent medical intervention. Breathlessness might suggest respiratory muscle involvement. Respiratory failure can occur in some diseases like Guillain-Barre syndrome, myasthenia gravis, and amyotrophic lateral sclerosis. Table  9.1 summarizes some of the common symptoms of diseases presenting with weakness.

9.2.2 Physical Examination The physical examination is an objective confirmation of the distribution and the severity of the muscle weakness. The first step is to observe the patient doing certain activities like raising arms, standing up from a chair, or writing. This will determine if the weakness is proximal, distal, or combined. A comprehensive neurological examination should follow with higher function examination and examination of cranial nerves. You may find ptosis, ophthalmoplegia, and/or poor gag reflex in myasthenia gravis patients. The next

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Table 9.1  Associated symptoms presented with muscle weakness Disease Dermatomyositis

Inclusion body myositis Myasthenia gravis

Lambert-Eaton syndrome Mixed connective tissue disease and overlap syndrome Rhabdomyolysis

step is performing detailed motor examination. This starts with inspection of the muscle bulk and determining whether if it is normal, atrophied, or hypertrophied. In addition to observation for any fasciculation that might suggest LMND, tone, power, reflexes, and gait should also be examined. Clear distinctions between signs of upper motor neuron disease (UMND) (hypertonia, hyperreflexia, and upgoing plantar response) and signs of LMND (for lesions from the anterior horn cell until muscles) (hypotonia, normal or low or absent reflexes, and equivocal or downgoing plantar response) should be made. Usually with signs of UMND, patients may present with hemiparesis, paraparesis, and quadriparesis or with variable locations in the central nervous system as in multiple sclerosis. Since weakness is a prominent sign present in both UMND and LMND, it is essential to assess the power and document the degree of weakness, as well as for proper future monitoring of this disease while on

Symptoms Skin rash, e.g., upper eyelids (heliotrope rash), erythema of the knuckles (Gottron rash), anterior chest (v sign), or back (shawl sign) Weight loss, anorexia, bleeding tendency, abnormal vaginal bleeding, chronic cough (malignancy). Frequent falls, dysphagia Squint, dysphagia Compression symptoms of thymoma (cough, SOB) Autonomic symptoms, e.g., dry mouth, impotence History of lung cancer Other connective tissue disease’s symptoms; arthritis, skin rash History of trauma, seizure, dark urine

Weakness

Generalized

Chronic illness: Anemia Heart failure Chronic liver disease Depression Fibromyalagia Sleep Disorders Endocrine Cause

Localized

Motor Neuron Disease

Polyneuropathy

Hemiparesis (cortical lesion, brainstem lesion, spinal chord lesion, demyelinating disease)

Upper motor lesion signs (see examination) Distal muscles weaker than proximal ± Sensory loss ± Change in metal status ± Craninal nerve involvement

Asymmetrical ± Sensory loss

Symmetrical ± Sensory loss

Distal

Proximal

Distal

Carpal Tunnel Diabetic Neuropathy Peripheral Nerve Injury

Brachial Plexopathy

HIV Toxins Diabetic Neuropathy

Paraparesis/Quadriparesis (spinal chord lesion, demyelinating disease, viral trauma)

Upper and/or lower motor neuron signs (see examination) Progressive weakness - Sensory level - Urinary and bowel incontince - Erectile dysfunction ± Neck Pain

Fig. 9.2  Clinical approach to weakness

Proximal & Distal

Amytrophic Lateral Sclerosis: Upper motor neuron signs Progressive weakness +wasting +Bulbar symptoms

Guillain-Barre Syndrome

Inherited Motor Neuron Disease Post Poliomyelitis: Lower motor signs Wasting Twitching

Myopathy: Gradual onset Symmetrical No sensory Deficit Associated with Malignancy Associated with cardiomyopathy

Proximal: Toxins Endocrine Inflammatory Muscular Dystrophies

Distal Genetic distal myopathies, inclusion body myositis

Neuromuscular: Fatigue No Sensory loss Fluctuating weakness Drooping of eyelids Double vision

9  Diagnostic Approach to Proximal Myopathy

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treatment. Clinical approach to weakness is illustrated in Fig. 9.2. Grades of power are shown in Table 9.2. Reflexes are usually intact in proximal myopathy, and any signs of abnormal reflexes suggest neurological cause. The last step in the neurological examination is examining sensory level. For example, in peripheral neuropathy loss of sensation is parallel to the weakness. After comprehensive neurological examination, a search for extra-muscular signs should follow. The examination of the face, hands, lower limbs, chest, and abdomen is important, since any abnormality can help in the differential diagnosis. Few signs of common diseases presenting with myopathy are shown in Table 9.3. There are certain associations essential to be recognized while performing the physical examination. These associations may easily reveal the diagnosis without spending efforts on unnecessary investigations. Changes in the mental status, for example, with muscle weakness may indicate electrolyte imbalance. Cardiovascular assessment may reveal signs of cardiomyopathy, which is associated with some inflammatory and herediTable 9.2  Grades of power 5 4 3 2 1 0

tary myopathies. Pulmonary assessment may reveal crackles of interstitial lung disease associated with some inflammatory myopathies. Lymph node examination is essential as malignancies are associated with a significant number of IID including lymphoma. Small joint examination is essential as well to detect any tenderness and/or swelling suggestive of rheumatoid arthritis (RA) and/or systemic lupus erythematosus (SLE)associated myopathies. Skin examination is helpful: signs like Gottron’s papules in dermatomyositis, erythema nodosum in sarcoidosis, and skin bronzing in adrenal insufficiency (see Dermatology chapter). Also a search for any signs possibly related to underlying malignancy like finger clubbing, fecal occult blood, and hepatosplenomegaly should be made. Table  9.4 lists findings with their most likely definitive diagnosis. The vital signs should be measured to exclude any life-threatening problems. Postural hypotension can be seen in autonomic neuropathy, e.g., in diabetes mellitus and Lambert-Eaton syndrome. Also, body mass index (BMI) should be measured to assess if the patient is underweight suggestive of a malignant disease process.

9.3

Normal muscle strength, full resistance Reduced, but still against resistance Further reduced, only against gravity Only moves with gravity Flicker of movement No movement

Differential Diagnosis of Proximal Myopathy

Several conditions cause proximal myopathy. Myopathies can be classified into idiopathic or acquired. The clinical history and physical exam-

Table 9.3  Common signs with specific myopathies Dermatomyositis

Overlap syndrome and MCTD

Lambert-Eaton syndrome Myasthenia gravis

Head and neck –  Upper eyelids (heliotrope ash) –  Lymphadenopathy or any mass (malignancy) –  Fish mouth, pinched nose (in scleroderma) –  Malar rash, discoid lupus (in SLE) –  Dry mouth and skin (autonomic neuropathy)

Hands –  Erythema of the knuckles (Gottron rash) –  Clubbing (lung cancer) Sclerodactyly, Raynaud’s (in scleroderma). Arthritis (in SLE) –  Clubbing (lung cancer)

SVC syndrome (thymoma)



Chest and abdomen –  Erythema of anterior chest (v sign), or back (shawl sign) –  Axillary lymphadenopathy, breast lump or abdominal mass Signs of lung fibrosis and serositis

–  Chest finding if there are complications for lung cancer e.g. pleural effusion, lymphadenopathy –

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Table 9.4  Correlation between findings and suggestive diagnoses of weakness Findings Acute focal weakness decreased muscle power, hyperreflexia, hypertonia, positive Babinski sign, ± sensory deficit, ± loss of bladder/bowel control Diffuse or localized peripheral weakness, muscle atrophy, fasciculations, hypotonia, loss of reflexes Asymmetrical distal weakness, muscle atrophy, hypotonia, loss of reflexes, sensory deficit “Glove and stocking” distribution Acute onset of combined weakness (ascending), fasciculations, loss of deep tendon reflexes, sensory deficit Facial weakness, fatigability, ptosis Symmetrical weakness of proximal muscles, muscle wasting, with some types, muscle tenderness, normal reflexes, no sensory level Symmetrical distal weakness, with myotonic contractions Cardiomyopathy, and proximal muscle weakness

Mental status changes with proximal weakness

Suggestive diagnosis Stroke, or spinal cord injury

ders causing weakness, such as SLE and RA, can occur in young and elderly persons. Figure  9.3 summarizes the differential diagnosis of proximal myopathy. Further details about these disorders will be mentioned briefly in this section.

Lower motor neuron disease

9.3.1 Toxins- and Drug-Induced Myopathy

Peripheral neuropathy Diabetic neuropathy

Considering toxin and drug exposure in the differential diagnosis of every single patient presenting with proximal myopathy is essential. The timely diagnosis allows for optimum recovery. There are many drugs that cause proximal myopathy, such as lipid-lowering drugs, glucocorticoids, antimalarial drugs, antiretroviral drugs, alcohol, and cocaine [1]. There is an acute presentation in drug-induced myopathy. Statin therapy associated with muscle problems is seen in approximately 10–25% of patients treated in clinical practice. Statin-induced myopathy can present as myalgia and myositis or sometimes is severe enough to cause rhabdomyolysis. The average onset of statin-induced myopathy is weeks to months. The only treatment is discontinuation of statin which results in resolution of muscle symptoms [3]. Glucocorticoids are a common cause of muscle weakness. Long-term use of glucocorticoids results in an insidious onset of proximal myopathy. Muscle enzymes are usually normal. Relief of the weakness occurs with lowering the dose of glucocorticoids [4]. Alcohol-induced myopathy generally follows a history of long-standing alcohol intake and/or consumption of large amount of alcohol. Table  9.5 summarizes pertinent features of the common causes of toxin- and drugs-induced myopathy.

Guillain-Barre syndrome

Myasthenia gravis Proximal myopathies

Myotonic dystrophy Inflammatory myopathies, hereditary myopathies Myopathy-­ inducing electrolyte disorder (calcium or magnesium)

ination are essential in identifying the presence of a myopathy and narrowing down the differential diagnosis. In adults a major cause of myopathy is medication like statins [1]. Myopathy due to endocrine causes, for example, thyroid disease, Cushing disease, and adrenal diseases, should be diagnosed promptly because treating the primary condition will result in resolution of the myopathy [2]. Inflammatory diseases typically affect older adults including both proximal and steroid responsive disorders like polymyositis and dermatomyositis and distal and proximal myopathies with less response to steroid like inclusion body myositis. Rheumatologic disor-

9.3.2 Endocrine Myopathy Hormones play an essential role in body metabolism. Deficiency or excess in most hormones will affect muscle metabolism. In endocrine-related muscle diseases, the presentation is more likely to be fatigue than true muscle weakness. The

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Polmyositis ~10 cases per million

Dermatomyositis

Idiopathic

INFLAMTORY

malignancy

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IBM

Children adult females Adult females

Characteristic rash Heliotpe periorbital

Adult males 50 ys Limp gridle

HEREDITARY

Begin insidiously and progress very slowly

facioscapulohumeral Glycogen & lipid storage disorder Corticosteroid

DRUGS & TOXINS

Acutely or subacutely and progress rapidly

Statin

Acquired

Alcohol Thyroid (hypo or hyper) ENDOCRINE MALIGNANCY

Hypokalemic periodic paralysis → Episodic weakness Osteomalecia

INFECTIOUS Miscellaneous

Sarcoidosis

Fig. 9.3  Differential diagnosis of proximal myopathy

Table 9.5  Features of toxin- and drug-induced myopathy Toxin/drug Alcohol

Effect on muscle Large consumption of alcohol will cause direct muscle necrosis

Glucocorticoid

Direct catabolic effect Chronic use of prednisone at a daily dose of ≥30 mg/day Risk increases in elderly and malignancy

Statin

Varying degrees of muscle necrosis Severe complications such as rhabdomyolysis and myglobinuria Dose and duration dependent

Characteristics Acute and chronic presentation Calf muscles Tenderness Swelling Generalized muscle cramps Proximal lower muscles Progressive Accompanied with atrophy No tenderness Myalgia Malaise Muscle tenderness Muscle pain may be related to exercise

Management Resolution with cessation of alcohol

Improved muscle strength within 3–4 weeks after lowering the dose

Muscle weakness will resolve with decreasing the dose or cessation of the statin

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serum CK level is often normal (except in hypothyroidism). Nearly all endocrine myopathies respond to treatment [5]. Abnormalities in thyroid hormone can lead to a wide range of muscle diseases. For example, hypothyroid patients have frequent muscle complaints such as cramps, pain, and weakness. Almost one third of hypothyroid patients present with proximal myopathy. They present mainly with shoulder and hip muscle weakness. Treatment by thyroid replacement usually leads to resolution of symptoms and laboratory abnormalities [6]. Proximal myopathy is a very common presentation in hyperthyroid patients and may be the only symptom of the disease. Bulbar, respiratory, and even esophageal muscles may be affected, causing dysphagia and aspiration. Other neuromuscular disorders may occur in association with hyperthyroidism including ­ hypokalemic periodic paralysis, myasthenia gravis, and a progressive ocular myopathy. Because proximal weakness is a presenting sign of hyperthyroidism and hypothyroidism, checking thyroid-stimulating hormone (TSH) is essential. Adrenal insufficiency causes muscle fatigue rather than true muscle weakness. Conn’s syndrome can lead to proximal myopathy which is related to hypokalemia [7]. Pituitary disorders like acromegaly if long-standing can cause myopathy [8]. Neuromuscular complications of diabetes mellitus (DM) are mainly due to neuropathy which can be presented as asymmetrical proximal weakness. Ischemic infarction of the thigh muscles can present with severely uncontrolled diabetes [9] (see Chap. 21 (Diabetes and Rheumatology)). Table 9.6 summarizes pertinent findings of myopathies caused by endocrine disorders.

9.3.3 Dystrophic Myopathies Dystrophic myopathies are a distinct group of inherited muscle disorders that generally present chronically. They are slowly progressive in nature resulting in muscle atrophy with exception of metabolic myopathies, where symptoms on occasion can be precipitated acutely. Each type of dystrophic myopathy has some characteristic

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structural abnormalities on muscle immunohistochemistry. Congenital myopathies present predominantly in the perinatal period. Some can present later in childhood, and these children may have a milder course of the disease. Multiple gene defects can give rise to similar clinical and ultrastructural phenotypes; thus, muscle immunohistochemistry should be tested to reach a final diagnosis. Table 9.7 shows the features of dystrophic myopathy [10].

9.3.4 Inflammatory Myopathies Inflammatory myopathies are a group of complex diseases of unknown etiology. The most common types are dermatomyositis, polymyositis, and inclusion body myositis. Table 9.8 represents the current classification for IIM.  The incidence of inflammatory myopathies is 5–10/million cases per year [11]. These diseases are characterized by progressive muscle weakness with extra-­ muscular organ involvement and high serum muscle enzymes. Generally there is a female predominance 2:1, but in inclusion body myositis, the opposite is seen as it is three times more common in males [12]. The main pathophysiology is related to autoimmunity, though recent studies show that the mechanism of muscle damage is multiple and complex [13]. The clinical features of inflammatory myopathy in general are muscle weakness occurring within weeks to months. The distribution of weakness is mainly proximal in dermatomyositis and polymyositis, but as the disease progresses, distal muscles may become affected. On the other hand, distal muscle weakness is the initial presentation of inclusion body myositis. The onset of polymyositis is usually after the second decade of life. Dermatomyositis has two peaks, the first peak at around 10–15 years of age and the second peak between 40 and 70  years. Inclusion body myositis occurs after the age of 50. Table  9.9 summarizes the pathological and clinical features of the most common IID. Dermatomyositis is known for its cutaneous manifestations. The rashes can precede, follow, or occur simultaneously with the myopathy.

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Table 9.6  Pathophysiology and characteristics of endocrine myopathies Endocrine disease Hypothyroidism

Pathophysiology Exact mechanism is unknown T4 is essential for metabolism Decrease in T4 leads to decrease in glycogenolysis which leads to impaired muscle function

Hyperthyroidism

Exact mechanism is unknown Impaired muscle function may be due to increased cellular metabolism and energy utilization, increased catabolism and protein degradation, and inefficient energy utilization

Hyperparathyroidism

Adrenal insufficiency

Primary hyperaldosteronism

Characteristics Proximal myopathy occurs in one third (shoulder and hip girdle muscles) Muscle cramps, stiffness, pain are common complaints More common in women Muscle hypertrophy is a rare sign (Hoffman’s sign) Delayed deep tendon reflexes Muscle weakness ± tenderness and atrophy in 60–80% of patients Presentation may be acute or chronic Two-thirds of patients with hyperthyroid myopathy report proximal weakness, mainly hip flexors and quadriceps Cramps are less common Atrophy is usually absent Bulbar symptoms may be present Associated with other neuromuscular diseases: Myasthenia gravis Periodic paralysis Progressive ocular myopathy 25% of patients will have insidious onset of proximal myopathy, legs more than arms Atrophy is a common feature Fatigue, muscle pain, and hyperreflexia are common 100% of patients present with weakness, but usually there is no objective proximal myopathy Weakness is a common complaint Weakness and paralysis are usually due to the hypokalemia

Cushing syndrome (see Glucocorticoid myopathy)

Gottron’s papules and heliotrope rash are pathognomonic features of dermatomyositis [14]. Dermatomyositis and polymyositis are also known to cause manifestations related to the cardiovascular system, respiratory system, and gastrointestinal system. Patients diagnosed with IID tend to have a higher risk of developing malignancies. Patients with dermatomyositis or polymyositis have an increased risk of developing malignancy. Those with dermatomyositis are three to six times more likely and those with polymyositis are two to four times more likely than the normal population to

develop ovarian, gastric, pancreatic, and lung cancer and non-Hodgkin lymphoma. Thus screening for malignancies is highly recommended in this population [15].

9.3.5 Myopathy Due to Infectious Disease Infectious diseases may cause an acute presentation of weakness with muscle cramps, myoglobinuria, and rhabdomyolysis. Among the infectious causes, viral infections are the most

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Table 9.7  Features of dystrophic myopathy Type of myopathy Duchenne

Becker’s Limb-girdle

Facioscapulohumeral muscular dystrophy (FSHD)

Myotonic dystrophy

Distribution Characteristic Proximal Age of onset 3–5 years Weakness starts in the trunk Spreads to arms and legs Gower’s sign Calf hypertrophy Wheelchair by ages 9–10 Cardiomyopathy Scoliosis/respiratory problems Cognitive impairment Proximal Age of onset 3–20 years Less severe than Duchenne Proximal Age of onset 3–20 years Shoulder and hip muscles Low back pain Sparing of the face Cardiac involvement Contractures No cognitive impairment Proximal Age of onset is variable (average 10–20 years) Infant form wheelchair by 9 years Severe facial weakness Inability to close eyes Inability to smile Weakness can involve shoulder and hips Early onset: Hearing loss, seizures, cognitive impairment Distal Age of onset is variable Most common adult-onset muscular dystrophy Type 1, type 2 Affects facial muscle, arms, legs Multisystem: Cardiac, cataract, sexual organs, cognitive impairment Excessive daytime sleepiness

Table 9.8 Classification of idiopathic inflammatory myopathies   1.  Primary idiopathic dermatomyositis   2.  Polymyositis or dermatomyositis with malignancy   3.  Juvenile dermatomyositis (or polymyositis)   4.  Inclusion body myositis   5.  Rare forms of idiopathic myositis     •  Granulomatous myositis     •  Eosinophilic myositis     •  Focal myositis     •  Orbital myositis

common. Myalgia is the most common symptoms, but can last up to 2–3  weeks. Usually myopathy due to viral infections is self-limiting,

Mode of inheritance X-linked

X-linked AR/AD

AD

AD

but severe cases may cause myoglobinuria and renal impairment. Human immunodeficiency virus (HIV) is an important differential when approaching myopathy; the condition is often referred to as HIV polymyositis. HIV polymyositis can be a presenting manifestation of HIV infection or can occur in later stages. Patients with HIV polymyositis may present with asymptomatic elevation of CK levels, or as severe muscle tenderness and muscle weakness. HIV-related myopathy appears to have a better prognosis than idiopathic inflammatory myopathies. See the treatment section for how to manage HIV polymyositis.

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Table 9.9  The pathogenetic mechanisms and clinical features of the most common IID Condition Dermatomyositis

Pathogenesis Humeral mediated process CD4 cells and B lymphocytes attack the vascular endothelium; result in necrosis of capillary and ultimately muscle atrophy

Age/sex 10– 15 years 40– 70 years F: M—2:1

Polymyositis

Cellular mediated process CD8 cytotoxic cells recognize MHC-1 on the muscle fiber, and this is the initiation of the necrotic process

Second decade of life F: M—2:1

Inclusion body myositis

The mechanism is poorly understood, but histopathology shows inflammatory cells surrounding myofibers and rimmed vacuoles, and some myofibers are attacked by CD8 cytotoxic cells

>50 years 3 times more in men

9.4

Diagnostic Approach

A thorough history and physical examination is the cornerstone to reach the diagnosis. Investigations should be tailored to screen for reversible causes of a myopathy (Fig. 9.4). When the cause of muscle weakness is unclear, appropriate testing should be performed, and it is recommended to start with blood tests including electrolytes (potassium, calcium, phosphate, and magnesium), thyroid-stimulating hormone (TSH) level, alkaline phosphatase and 25 (OH) vitamin D level, and HIV [16].

9.4.1 Muscle Enzyme The measurement of serum levels of muscle enzymes is of critical value for the evaluation and monitoring of muscular disorders. Creatine

Clinical features Symmetrical proximal muscle weakness Pathognomonic: Heliotrope (purple) Periorbital edema; violaceous papules (Gottron’s papules) or macules (Gottron’s sign) Diagnosis by exclusion No skin manifestation Associated with HIV Histopathology is considered the most effective way to establish the diagnosis of PM

Both dermatomyositis and polymyositis: •  10% have interstitial lung disease (may lead to respiratory failure and death) •  Increase rate of malignancy •  Dysphagia, nasal regurgitation, and/or aspiration with increased age •  Cardiac involvement in the form of myocarditis, conduction defects, and arrhythmias •  Constitutional symptoms

Insidious onset and progressive asymmetric distal weakness with wrist and index finger flexors weaker than extensors. Associated with early atrophy and poor response to steroid

kinase (CK), lactate dehydrogenase (LD), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and aldolase are the serum muscle enzymes that are measured in clinical practice. In patients with suspected myopathy who do not demonstrate CK elevation, testing for aldolase can be helpful, but it is less sensitive and less specific [17]. Approach to high level of CK is demonstrated thoroughly in Table  9.10. It must be noted that CK elevation is, however, not specific to myopathy and further testing should be performed in a comprehensive approach. Table  9.11 shows the differential diagnosis to high CK level. While diagnosing myocardial infarction, besides symptoms and abnormal ECG findings, there will be rise in CK-MB, the isoenzyme of CK, electrophoretically distinguished and high in concentration in the cardiac tissue. However, it is neither specific nor sensitive as troponins [18].

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Statin induced muscle symptoms

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Check for reversible causes

Drug interactions, hypothyroidism, AKI, CKD, CLD and Vitamin D deficiency

Assess risk and benefit for cardiovascular risk

If CK 10 ULN even without symptoms Discontinue statin Persistent symptoms despite adjustment of doses and switching to pravastatin, lovastatin, with CK >4 ULN

Fig. 9.4  Approach to statin-induced myopathy

CK might be falsely elevated secondary to ethnicity (can be high in Afro-Caribbean men), exercise (can remain elevated for up to 72  h), intramuscular injections, needle electromyography (EMG), medications, hypothyroidism, and motor neuron disease [16].

9.4.2 Rhabdomyolysis Muscle injury due to vigorous exercise, medication, infection, and metabolic derangements can cause rhabdomyolysis. Severe myalgia, weakness, and red to brown urine due to m ­ yoglobinuria are classical initial presenting features. Rise of CK levels is typically seen after 2–12 h of injury and reaches its maximum within 24–72  h. A decline is usually seen within 3–5 days of cessation of muscle injury. Myoglobinuria is present in 50–75% of patients at the time of initial evaluation. Thus it is recommended to perform routine dipstick urine analysis in any patient with

extremely elevated CK level and myopathy. There are serious metabolic derangements that complicate this massive muscle destruction in the body. Electrolyte imbalance and acute renal failure are serious examples.

9.4.3 Other Tests In addition to CK, to diagnose rheumatologic myopathy, erythrocyte sedimentation rate (ESR) C-reactive protein (CRP), antinuclear antibody assay (ANA), rheumatoid factor, anti-doublestranded DNA, antiphospholipid antibodies, and anti-centromere antibodies should be ordered. In case of inflammatory myopathy, check for anti-Jo1 antibody, directed against histidyl-tRNA synthetase. Recognition of antiJo1 syndrome is important because such patients can develop extra-muscular features, such as interstitial lung disease, Raynaud’s phenomenon, and arthritis [19].

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Table 9.10  Approach to high CK level Episodic Range from normal to rhabdomyolysis Endocrine Hypothyroidism Hyperthyroidism Cushing’s syndrome Acromegaly Electrolyte imbalance Metabolic myopathies Glycogen and lipid storage disease Carnitine palmitoyl transferase (CPT) Muscle phosphorylase deficiency

Periodic paralysis Primary hypokalemic periodic paralysis

Mild 3–four-fold ULN Drugs Antimalarial, cholesterol-lowering drugs (statins), cocaine, alcohol, colchicine → 10- to 20-fold

Systemic vasculitis Polyarteritis nodosa Wegener’s Behçet’s disease Sarcoidosis Connective diseases Rheumatoid arthritis Systemic lupus erythematosus Sjögren’s syndrome Scleroderma Specific autoantibodies anti-U1 RNP and anti-PM/Scl Inclusion body myositis 80 percent of patients

High 100 fold ULN Rhabdomyolysis Acute, massive muscle injury due to: Trauma, seizures, electrolyte imbalances, infections The degree of myoglobinuria might Correlate with the risk of acute renal failure CK levels decrease rapidly to normal after managing the cause Infectious myopathies Viral (EBV, HIV), bacterial, mycobacterium, fungal, parasitic

Polymyositis & dermatomyositis Abnormal EMG and muscle biopsy findings correlation between the height of CK elevation at diagnosis and the severity of disease

Dystrophic myopathies Limb-girdle dystrophies Facioscapulohumeral dystrophy, myotonic dystrophy CK levels peak by age 2 and then progressively fall, often to the normal range, as more and more muscle is replaced by fat and fibrosis Motor neuron disease (amyotrophic lateral sclerosis)

Table 9.11  Differential diagnosis to high CK level   •  Differential diagnosis of CK with weakness     –  Inflammatory     –  Metabolic     –  Endocrine     –  Drug induced     –  Infectious (viral)

•  Differential diagnosis of CK without weakness –  Strenuous exercise –  After EMG studies –  Trauma –  Post-surgery –  Intramuscular injections –  Metabolic and congenital myopathy –  Medications –  Race (African Americans)

9.4.4 Electromyography (EMG) Electromyography (EMG) is a test that is used to record muscle electrical activity and assess the nerves that control the muscles. An abnormal electromyogram can indicate a neuropathy or neuromuscular disease. Characteristic EMG findings of myopathy include short duration and decreased amplitude of action potential unlike neuropathies that are characterized by increased duration and amplitude of action potential.

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Although there are no pathognomonic features that distinguish different forms of myopathy, EMG can help distinguish inflammatory from non-inflammatory forms of myopathy. Normal EMG examination, however, would not exclude myopathy [18]. In case of polymyositis, the site of muscle biopsy should be opposite to where the EMG was conducted [16].

9.4.5 M  uscle Magnetic Resonance Imaging (MRI) MRI evaluates deep muscles not readily accessible by EMG and plays a role in the diagnostic process by identifying subclinical signs of muscle involvement. Fat-suppressed and short tau inversion recovery techniques differentiate between active myositis, pictured as edema, and chronic inactive myositis in patients with inflammatory myopathy, presented as fat [20]. A secondary role for muscle MRI is to provide information about the best site for muscle biopsy by showing which muscles are involved in the myopathic process.

9.4.6 Muscle Biopsy Establishing the diagnosis of IID is essentially based on histopathological grounds. There are currently advanced therapies that can be used effectively in these patients. The justification of using these drugs or even steroids should be based on muscle biopsy. Open surgical biopsy is preferable to closed needle biopsy because of the patchy nature of inflammation in PM and so that adequate tissue could be obtained. However, in some circumstances, the biopsy is performed by expert radiologists. Muscle biopsy is a reliable instrument in the diagnosis of PM in 85% of the patients [18]. It is an outpatient procedure that may cause pain, bleeding, infection, or sensory loss. No special preparation is required other than that patients should discontinue using anticoagulants before the procedure [21]. The best muscles to biopsy are those moderately affected by the disease process but not atrophied. Previous sites of injections, EMG

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examination, or trauma should be avoided. The most common biopsy sites are the deltoid, quadriceps for proximal myopathy, and gastrocnemius for distal myopathies. Technology using genetic markers is advancing rapidly. In inflammatory myopathies, immune staining for major histocompatibility classes I and II (MHC-I/II) is upregulated in myofibrils, whereas MHC-I immune staining alone is non-­ specific [22].

9.4.7 Screening for Malignancy Idiopathic inflammatory myopathies PM and DM have positive relation to malignancy; retrospective studies’ results justify CT of the chest, abdomen, and pelvis in addition to age-appropriate screening tests such as colonoscopy and mammography for any patient newly diagnosed. This is shown in Southeast Asia where input of otolaryngologists is invaluable due to the higher incidence of nasopharyngeal carcinoma for DM patients. Recent advances in understanding of pathogenesis of idiopathic inflammatory myopathies have led to discovery of biomarkers like type 1 interferon and myeloid cell signatures to distinguish active disease from chronic injury [17].

9.4.8 Genetic Testing Genetic testing is becoming increasingly useful in confirmation of patient with muscular dystrophies and heritable myopathies. These mutations can be identified through peripheral blood DNA analysis. Molecular testing often eliminates the need for muscle biopsy.

9.5

The Management of Myopathy

9.5.1 Inherited Myopathy For most patients with congenital myopathy or muscular dystrophy, the treatment is mainly supportive. Physical therapy, occupational therapy,

9  Diagnostic Approach to Proximal Myopathy

management of contractures, nutrition, and genetic counseling together play a role in managing congenital myopathies. In patients with Duchenne muscular dystrophy, treatment with prednisone has been shown to improve strength and muscle bulk and slow the rate of natural progression of the disease. Patients should also be monitored over time for complications related to kyphoscoliosis or involvement of cardiac, respiratory, or bulbar muscles. Finally, genetic counseling should be offered to all patients with inherited myopathy and their family members.

9.5.2 Acquired Myopathy Management of proximal myopathy depends on underlying etiology. Treatable causes should be sought and treated accordingly. Discontinuation of offending drug is likely to improve symptoms in patients with drug-induced myopathy, e.g., statins [5]. Dose reduction should be considered for those patients in whom abrupt discontinuation of drug may not be possible, e.g., steroid myopathy [6]. In HIV-related myositis, treatment with the combination of highly active antiretroviral therapy (HAART) and steroids may be beneficial. Treatment of IIM is largely empirical because of paucity of well-controlled trials. Current evidence is mostly based on retrospective or open prospective trials involving small numbers of patients. Corticosteroids are the cornerstone in the treatment of PM and DM [19, 20]. In the absence of placebo-controlled trials, the optimal initial dose and duration of therapy are uncertain, but patients are generally started on 0.75–1 mg/ kg body weight/day of prednisolone. Intravenous pulse methylprednisolone is initially considered for those with cardiac, respiratory, or pharyngeal muscle involvement to obtain quicker response. Because maximal improvement may not be seen for several weeks, the usual practice is to start tapering the dose of prednisolone only after about 4–12  weeks, guided by clinical improvement. Many patients relapse when corticosteroids are discontinued, and therefore, a maintenance dose of 5–10  mg/day is often required for several

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years. About a third of patients with PM or DM, and those with IIM, might fail to show any response to prednisolone. Second-line immunosuppressive drugs are tried in patients who do not respond to corticosteroids alone and in those with progressive disease and internal organ involvement. Choice of drug is largely empirical and depends on disease severity, extra- muscular manifestations, and personal experience of treating physician, again because of paucity of well-­ conducted trials. Azathioprine [23] or methotrexate is usually preferred. Intravenous immunoglobulin (Ig), the only agent for which there is positive evidence from randomized placebo-controlled trial [21, 24], is especially useful for patients with dysphagia and treatment-resistant DM.  Intravenous Ig is, however, expensive and limited in availability. Cyclophosphamide, given as monthly intravenous pulses for 3–6 months, is also an option for patients with respiratory muscle weakness, interstitial lung disease, or cardiac involvement [25]. Plasmapheresis has also been studied, but was not found to be helpful in a double-blind placebo-­ controlled trial [26]. Rituximab, a CD20 monoclonal antibody that depletes B cells, has been reported to have a favorable effect in small open-­ label uncontrolled trials [27, 28]. A new double-­ blind, placebo-phase trial in refractory adult and pediatric myositis using rituximab revealed good results [29]. Tumor necrosis factor inhibitors such as infliximab, adalimumab, and etanercept are ineffective in treating IID and may cause deterioration or trigger the disease [30]. Other biological agents that may be considered as experimental treatments include alemtuzumab, which is reportedly effective in polymyositis [31], and anti-complement C3 (eculizumab), which may be effective for the treatment of dermatomyositis. Overall, the long-term outcome of inflammatory myopathies has substantially improved, with a 10-year survival rate of more than 90% . Table  9.12 shows a step-by-step approach in the management of IID [32]. Input of physiotherapist is also valuable because randomized controlled trials among patients with IIM have demonstrated that exercise therapy, adapted to the patient’s condition, is

206 Table 9.12 Approach to treatment of inflammatory myopathies

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7. Cicala MV, Mantero F. Primary aldosteronism: what consensus for the diagnosis. Best Pract Res Clin Endocrinol Metab. 2010;24:915–21. https://doi. Clinical situation Treatment for IID org/10.1016/j.beem.2010.10.007. New-onset disease Prednisone (0.75–1 mg / 8. Del Porto LA, Liubinas SV, Kaye AH.  Treatment kg) for 4–12 weeks of persistent and recurrent acromegaly. J Clin Intravenous Weakness is severe + Neurosci. 2011;18:181–90. https://doi.org/10.1016/j. glucocorticoids cardiac, respiratory, jocn.2010.10.003. (1000 mg/day) for pharyngeal involvement 9. Yildirim Donmez F, Feldman F. Muscle compromise 3–5 days and then switch in diabetes. Acta Radiol. 2008;49:673–9. https://doi. to oral org/10.1080/02841850802105269. If patient responds to Start a glucocorticoid-­ 10. Emery AE.  The muscular dystrophies. Lancet. glucocorticoids sparing agent 2002;359:687. •  Azathioprine 11. Briani C, Doria A, Sarzi-Puttini P, Dalakas •  Methotrexate MC. Update on idiopathic inflammatory myopathies. Autoimmunity. 2006;39:161e70. Intravenous immune If response to 12. Yazici Y, Kagen LJ. Clinical presentation of the idioglobulin (2 g/kg in glucocorticoids is pathic inflammatory myopathies. Rheum Dis Clin divided doses over insufficient North Am. 2002;28:823–32. 2–5 days) 13. Targoff IN.  Immune manifestations of inflamConsider initiating If response to matory muscle disease. Rheum Dis Clin N Am. treatment with rituximab glucocorticoids and 1994;20:857–80. intravenous 14. Kovacs SO, Kovacs SC. Dermatomyositis. J Am Acad immunoglobulin is Dermatol. 998(39):899–920. insufficient 15. Sigurgeirsson B, Lindelof B, Edna O, Allander Dalakas, Marinos C. “Inflammatory muscle diseases.” E. Risk of cancer in patients with dermatomyositis or New England Journal of Medicine 372.18 (2015): polymyositis. N Engl J Med. 1992;326:363–7. 1734–1747 16. Ghaoui R, Clarke N, Hollingworth P, Needham M. Muscle disorders: the latest investigations. Intern Med J. 2013;43(9):970–8. beneficial and safe [33]. Benefits of exercise not only include improved muscle endurance, 17. Suresh E, Wimalaratna S. Proximal myopathy: diagnostic approach and initial management. Postgrad strength, and functional abilities but also prevent Med J. 2013;89(1054):470–7. muscle wasting and fibrotic contractures. 18. Weisberg LA, Strub RL, Garcia CA, Strub AC. Diseases of muscle and neuromuscular junction. In: Essentials of clinical neurology: University Park Acknowledgments The authors would like to thank Press; 1983. Haytham Abbas, MD, for his contributions to this chapter 19. Inflammatory myopathies. Postgrad Med J. in the previous edition. 2006;82:417–24. 59 20. Greenberg SA. Inflammatory myopathies: evaluation and management. Semin Neurol. 2008;28:241–9. 21. Dalakas MC, Illa I, Dambrosia JM, et al. A controlled References trial of high-dose intravenous immune globulin infusions as treatment for dermatomyositis. N Engl J 1. Dalakas MC.  Toxic and drug-induced myopathies. J Med. 1993;329:1993–2000. Neurol Neurosurg Psychiatry. 2009;80:832–8. 2. Horak HA, Pourmand R.  Neurol Clin. 22. Chawla J. Stepwise approach to myopathy in systemic disease. Front Neurol. 2011;2:49. 2000;18(1):203–13. 3. Thompson PD, Clarkson P, Karas RH.  Statin-­ 23. Bunch TW.  Article first published online: 23 Nov 2005. https://doi.org/10.1002/art.1780240107. associated myopathy. JAMA. 2003;289:1681. 24. Wang DX, Shu XM, Tian XL, et  al. Intravenous 4. Afifi AK, Bergman RA, Harvey JC.  Steroid myopa- immunoglobulin therapy in adult patients with polythy. Clinical, histologic and cytologic observations. myositis/dermatomyositis: a systematic literature Johns Hopkins Med J. 1968;123:158. review. Clin Rheumatol. 2012;31:801–6. 5. Horak HA, Pourmand R.  Endocrine myopathies. Neurol Clin. 2000;18:203–13. https://doi. 25. Al-Janadi M, Smith CD, Karsh J. Cyclophosphamide treatment of interstitial pulmonary fibrosis in polymyorg/10.1016/S0733-8619(05)70186-9. ositis/dermatomyositis. The Journal of Rheumatology, 6. McKeran RO, Slavin G, Ward P, et  al. Hypothyroid 1989;16(12):1592—6. http://europepmc.org/abstract/ myopathy. A clinical and pathological study. J Pathol. MED/2625692. 1980;132:35.

9  Diagnostic Approach to Proximal Myopathy 26. Miller FW, Leitman SF, Cronin ME, et al. Controlled trial of plasma exchange and leukapheresis in polymyositis and dermatomyositis. N Engl J Med. 1992;326:1380–4. 27. Levine TD.  Rituximab in the treatment of dermatomyositis: an open-label pilot study. Arthritis Rheum. 2005;52:601–7. 28. Chung L, Genovese MC, Florentino DF. A pilot trial of rituximab in the treatment of patients with dermatomyositis. Arch Dermatol. 2007;143:763–7. 29. Rituximab in the treatment of refractory adult and juvenile dermatomyositis and adult polymyositis. Arthritis Rheum. 2013;65(2):314–24. https://doi. org/10.1002/art.37754. 30. Brunasso AMG, Aberer W, Massone C. New onset of dermatomyositis/polymyositis during antiTNF-α therapies: A systematic literature review.

207 The Scientific World Journal; 2014. https://doi. org/10.1155/2014/179180. 31. Thompson BEN, Corris P, Miller JAL, Cooper RG, Halsey JP, Isaacs JD, Rheumatologist C. Alemtuzumab (Campath-1H) for Treatment of Refractory Polymyositis. The Journal of Rheumatology. 2008;35(10):2080–2. http://www. jrheum.org/content/35/10/2080.abstract. 32. Yin G, Liang Y, Deng R, Wang Y, Xie QB, Zuo C. [Survival analysis and risk factors for survival in idiopathic inflammatory myopathies: a retrospective cohort study]. Sichuan Da Xue Xue Bao Yi Xue Ban. 2013;44(5):818–22. Chinese. PMID: 24325120. 33. Habers GE, Takken T.  Safety and exercise training in patients with an idiopathic inflammatory myopathy: a systematic review. Rheumatology (Oxford). 2011;50:2113–24.

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Bones and Rheumatology

10

Altaf Abdulkhaliq

10.1 Introduction Bone is a target tissue in many inflammatory diseases including rheumatic diseases such as rheumatoid arthritis (RA), ankylosing spondylitis (AS), systemic lupus erythematosus (SLE), and psoriatic arthritis. A relationship between inflammation and bone disease has been established in a variety of clinical settings and animal models of inflammatory disease [1–4]. It has been established that the nature of the inflammatory disease can influence on the extent and type of bone disease and that even a small rise in the level of systemic inflammation can impact on bone remodeling and increase fracture risk [5]. The inflammatory joint disorders, namely, rheumatic diseases, are usually accompanied with extra-articular side effects, mainly bone loss, or osteoporosis that would result in an increased risk of fractures and deformities, which are in turn associated with increased morbidity and mortality [6]. Therefore, such types of musculoskeletal diseases are considered as one of the major causes of disability around the world and can explain the enormous cost of the musculoskeletal conditions to the community.

A. Abdulkhaliq (*) College of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia e-mail: [email protected] © The Author(s) 2021 H. Almoallim, M. Cheikh (eds.), Skills in Rheumatology, https://doi.org/10.1007/978-981-15-8323-0_10

In order to easily understand the underlying pathology and mediators that affect bones in rheumatic conditions, a brief overview on bone structure, biology, physiology, and essential molecular mechanism and signaling pathways needs to be explained clearly.

10.2 Objectives 1. To explain the underlying bones pathology among patients with rheumatic diseases. 2. To identify the common bone lesions occur with rheumatic diseases. 3. To recognize the serious impact of developing secondary osteoporosis among patients with rheumatic diseases. 4. To provide an updated approach for prevention and treatment of glucocorticoid-induced osteoporosis (GIOP) and bone fractures among patients with rheumatic diseases receiving glucocorticoids.

10.3 Bone Structures Bone is a dynamic and highly specialized form of connective tissue, in which the extracellular components are mineralized, thus giving the property of marked rigidity and strength while retaining some degree of elasticity. Bone represents a store of calcium and other inorganic ions 209

210 Fig. 10.1 Components of bone structure

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EXTRACELLULAR MATRIX

BONE CELLS

OSTEOCYTIS: derived from osteoblast and response to mechanical strain and maintinance of the bony matrix OSTEOBLASTS: derived from mesenchymal stem cells. responsible for the synthesis of the organic component of bone matrix OSTEOCLASTS: derived from heamatopoietic of macrophage lineage. resolve collagenhaving receptor for calcitonin and thyroid hormone.

and actively contributes to the maintenance of calcium homeostasis. Two types of bone can be identified macroscopically: compact or cortical bone and cancellous or trabecular bone. Microscopically both types of bone have the same histological structure. Like other supporting connective tissues, bone is composed of cells and extracellular matrix that is made up of 35% of organic component and 65% inorganic component [7]. The inorganic part consists of calcium and phosphorus in hydroxyapatite crystal form, while the organic component consists of type 1 collagen and ground substance containing proteoglycan aggregates and several specific structural glycoproteins [8] (Fig. 10.1).

10.4 B  one Remodeling and Bone Cells Bone remodeling is the lifelong process whereby old bone is removed by bone resorbing cells and subsequently replaced by new bone via the action of bone-forming cells to maintain the bone structure. Bone remodeling occurs normally in all individuals, and in adults about 25% of trabecular and 3% of cortical bone is replaced by such process each year [9]. Bone remodeling also helps

65% IN ORGANIC (BONE MENIRALS) COMPONENTS: Consists of calcium and phosphorus in hydroxyapatite crystal form

35% ORGANIC COMPONENTS: Consists of: - Type-1 collagen (main protein, and - Non collagen proteins of ground substances containing proteoglycan aggregates and several specific structural glycoproteins (osteopontin, osteocalcin and fibronectin).

to maintain mineral homeostasis via the liberation of calcium and phosphorus into the circulation. The remodeling process occurs at discrete sites on cortical and cancellous bone surfaces and involves the integrated and sequential actions of osteoclasts (bone resorbing cells) and osteoblasts (bone-forming cells), comprising anatomic structures known as basic multicellular units (BMUs).

10.4.1 Bone Cells Mesenchymal stem cells have the potential to differentiate into various cell types including osteoblasts, chondrocytes, adipocytes, myoblasts, and fibroblasts. Determination of the final fate of the differentiation process is determined by and depending on the signaling transcription pathways that are activated during the initial phase of differentiation of mesenchymal progenitor cells [10, 11]. Among the important signaling pathways that are responsible to direct the differentiation into osteoblast lineage are the mitogenactivated protein kinase (MAPK) and protein kinase A ­ (PKA)-dependent pathway [12] and Wnt-signaling pathway with its related β-catenin protein [13, 14]. Moreover, of the transcriptional factors, at least two are shown to be absolutely

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essential for osteoblast differentiation from mesenchymal precursors including Runx2 [15–17]. The plasma membrane of activated osteoblast is rich in alkaline phosphatase and exhibits receptors for parathyroid hormone (PTH) [18], whereas the nuclei have receptors for estrogens [19], vitamin D3 [20], and glucocorticoids [21], which all are involved in the regulation of osteoblast differentiation and activity. Osteoblasts contribute in the synthesis and secretion of new organic part of bone matrix (but not yet mineralized), called osteoid, between the secreting osteoblast layer and in contact with older bone matrix of previously formed bone. This process is referred to as bone apposition and is completed by further mineralization of the newly formed bone matrix (deposition of calcium salts into matrix), a process regulated by osteoblast too. At the end of the secreting period a

BMPs

Mesenchymal osteoblast progenitor

b

of osteoblasts, those osteoblasts are embedded within the bone and differentiated into osteocytes. Osteoclasts originate from hematopoietic stem cells (HSCs), precisely from cells of the colony-forming unit of macrophage (CFU-M) that differentiate to multinucleated, giant, motile cells on stimulation with macrophage colony-­ stimulating factor (M-CSF) and receptor activator of nuclear factor-kappa B “NFkB” ligand (RANKL) (Fig. 10.2). Firstly, the osteoclast progenitors proliferate and differentiate into mononuclear preosteoclasts and then fuse with each other to form multinucleated cells. The terminal differentiation in this lineage is characterized by acquisition of mature phenotypic markers, such as the calcitonin receptor, tartrate resistant acid phosphatase (TRAP), and integrin αvβ3 [22]. The mature and active osteoclasts are characterized by a moderate

clast PTH, Vit D, IGFs, BMPs, Wnts

Osteoblast precursor

Active osteoblast Collagen (I) Alkaline phosphatase Osteocalcin, osteopontin Bone sialoprotein

M-CSF

Commitment Hematopoietic osteoclast progenitor

M-CSF RANK Ligand IL-1, IL-6

RANK Ligand

Differentiation Osteoclast precursor PU-1+

RANK Ligand IL-1

Fusion Mononuclear osteoclast c-fos+ NKkB+ TRAF+

Fig. 10.2  Pathways regulating the development of (a) osteoblasts and (b) osteoclasts. Hormones, cytokines, and growth factors that control cell proliferation and differentiation are shown above the arrows. Transcription factors and other markers specific for various stages of development are depicted below the arrows. BMPs, bone morphogenetic proteins; Wnts, wingless-type mouse mammary tumor virus integration site; PTH, parathyroid hormone;

Quiescent osteoclast

Active osteobalst c-src+ b3 integrin+ PYK2 kinase+ Cathepsin k+ TRAF+ Carbonic angydrase II+

Vit D, vitamin D; IGFs, insulin-like growth factors; Runx2, Runt-related transcription factor 2; M-CSF, macrophage colony-stimulating factor; PU-1, a monocyteand B lymphocyte-specific ets family transcription factor; NFB, nuclear factor B; TRAF, tumor necrosis factor receptor-associated factors; RANK ligand, receptor activator of NFB ligand; IL-1, interleukin-1; IL-6, interleukin-­6 [24]

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rough endoplasmic reticulum, a well-developed Golgi apparatus, and abundant mitochondria, while the surface of their plasma membrane facing bone matrix is having ruffled border (clear or sealing zone), which is devoid of organelles but rich in actin microfilaments that form a ring of contractile protein serving to attach the cell to the bone surface via integrin receptors during the resorptive process [8]. The clear zone is a site of adhesion of the osteoclast to the bone matrix and creates a microenvironment where bone resorption takes place. From the ruffled border, osteoclasts secrete collagenase (and other proteolytic enzymes) and pump protons (low pH) into microenvironment and thus promoting the localized digestion of matrix and the dissolving of bone mineral (calcium salt crystal), respectively. Several systemic and local factors have influenced osteoclasts and their bone resorption ability. In normal physiological conditions, the osteoclast activity is highly balanced by those factors. However, in pathological conditions, this balance becomes disturbed such as during exces-

sive activation of the immune system, due to the secretion of additional pro-inflammatory cytokines, produced mainly by activated T cells [23].

10.4.2 The Remodeling Cycle The remodeling cycle is comprised of four distinct phases including activation, resorption, reversal, and formation phase (Fig. 10.3). Bone remodeling starts with activation of the lining cells via increasing the surface expression of RANKL. In the activation phase, RANKL interacts with its receptor RANK, thus triggering the recruitment of osteoclast progenitors to bone where they proliferate and differentiate into osteoclasts and attach tightly to the bone matrix. Next is the resorption phase, when the activated osteoclasts possess ruffled borders under which the proteolytic enzymes are secreted and the hydrogen ions are pumped resulting in digestion of collagens and dissolving the mineralized

Activation phase

Resorption phase

OCL

preOCLs

BMPs

Lining cells

Quienscene

FGFs TGFβ

Reverse cells

Osteoid Mineralization

Formation phase

Fig. 10.3  Process and phases of normal bone remodeling [26]

OBLs

Reverse phase

10  Bones and Rheumatology

matrix with the formation of a resorption cavity and allowing the release of several growth factors usually stored in the bone matrix. In addition, there is an accumulation of high concentration of calcium that directly controls osteoclasts activity resulting in cell retraction [25] and movement of osteoclasts across the bone surface to resorb a new area. At the end of this stage, osteoclasts undergo apoptosis after a life span of about 3 weeks, and thus the process of remodeling requires the continual production of osteoclast precursors. In the reversal phase, the remnant debris of matrix degradation will be removed, while the released growth factors including bone morphogenetic proteins (BMPs), fibroblast growth factors (FGFs), and transforming growth factor-β (TGFβ) are likely to be responsible for recruitment of osteoblasts to cover the bottom of the resorption cavity, forming osteoid tissue until the cavity is filled. In the final formation phase of bone remodeling, osteoblasts initially synthesize the organic matrix and then preside over its mineralization, thus completing the bone remodeling process. Toward the end of this process, some osteoblasts start to flatten and become quiescent lining cells; others become embedded in the matrix and differentiate into osteocytes, while the remaining of osteoblasts will undergo programmed cell death.

10.4.3 Factors Influencing Remodeling The rate at which new osteoblasts and osteoclasts are supplied and the timing of apoptosis of these cells are crucial determinants of bone remodeling. The development of osteoclasts and osteoblasts is controlled by growth factors and cytokines produced in the bone marrow microenvironment and is modulated by systemic hormones and immunological mechanisms [27–30]. Certain signaling pathways, systemic hormones, pro-inflammatory cytokines, and growth factors are considered as fundamental regulators of bone remodeling. Taken together, positive stimulator of osteoblast activity includes PTH, vitamin D3, IGFs, BMPs, and Wnt signaling, while those that

213

promote osteoclast activation are monocyte-­ macrophage colony-stimulating factor M-CSF, RANKL, IL-1, and IL-6. Eventually, the recent discovery of osteoprotegerin (OPG) and the subsequent identification of its cognate ligand, OPG ligand (OPGL or RANKL), have illuminated our understanding of the molecular basis that links between osteoblastogenesis and osteoclastogenesis and thereby the rate of bone remodeling upon which other inputs (hormonal, biomechanical, etc.) operate.

10.4.4 RANK/RANKL/OPG System Despite that the principal function of the osteoblasts is to synthesize bone matrix proteins and to enhance bone mineralization, osteoblasts also play a crucial role in osteoclast biology that has been clearly demonstrated by the release of key molecules, which regulate osteoclastogenesis and bone resorption. Of these regulators are RANKL which is expressed on the surface of the osteoblast and interact with its receptor RANK [22] to mediate signals for osteoclast proliferation, differentiation, activation, and function [31] (Fig. 10.4), while OPG is acting as a decoy receptor for RANKL [32], noting that the OPG/RANK/ RANKL system accounts only for signaling of osteoblasts to osteoclasts. The human RANK is a polypeptide of 616 amino acids, related to the type 1 transmembrane protein class [33], and is expressed in various tissues such as the skeletal muscle, liver, and small and large intestines. Among bone cells RANK-­mRNA is exclusively expressed in osteoclast precursor cells [22, 32]. On the other hand, RANKL is a TNF-related cytokine that exists in both transmembrane, the predominant form, and soluble (cleaved) forms [22]. The gene expression of RANKL can be found abundantly in the skeleton and lymphoid tissues and is produced by osteoblasts, bone marrow stromal cells, and other cells under the control of various pro-resorptive growth factors, hormones, and cytokines. Moreover, osteoblasts and stromal cells produce OPG, which binds to and thereby inactivates RANKL.

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CFU-M RANKL OPG Pre-Fusion Osteoclast

RANK Inhibited by OPG

Multinucleated Osteoclast

Growth Factors Hormones Cytokines OPG

Mature Osteoclast

RANKL

Osteoblast Lineage

Activated osteoclast

Bone

Fig. 10.4  Mechanisms of action for OPG, RANKL, and RANK [34]

Collectively, RANKL is of great importance for the development and function of osteoclasts through binding to its transmembrane-signaling receptor RANK [35]. RANK-RANKL interactions lead to pre-osteoclast recruitment, fusion into multinucleated osteoclasts, osteoclast activation, and osteoclast survival. These effects are very selective to bone and can be inhibited by the natural, soluble, decoy receptor OPG [32]. OPG is considered as a humoral regulator of bone resorption. It blocks osteoclast maturation and differentiation, and subsequently it can protect the bone from both normal osteoclast remodeling and ovariectomy-associated bone loss [36]. Certain human adult tissues showed a high level of OPG mRNA expression, namely, the heart, the bone, the placenta, and the thyroid gland [37]. It has been demonstrated that OPG expression is upregulated in various human osteoblastic cell systems by 1,25-dihydroxyvitamin D3, bone morphogenetic protein-2 (BMP-2), pro-­inflammatory cytokines such as interleukin-1 (IL-1) [38], estrogen [39], as well as transforming growth factor-β (TGF-β) [40]. However, some discrepancies were noticed in the effect of these modulators on the expression of the OPG

mRNA and OPG protein levels depending on the species of the cells used and on the stage of osteoblastic differentiation. In contrast, it has been established that glucocorticoids downregulate the OPG transcript in human osteoblast and in human marrow stromal cells [41, 42], and they can suppress OPG production resulting in acceleration of osteoclastic bone resorption [43].

10.5 M  ediators of Bone Loss in Rheumatic Diseases Systemic bone loss in rheumatic diseases occurs as a result of several factors including direct effects of inflammation, poor nutrition, reduced lean body mass, immobility, and the effects of therapeutic agents, specifically glucocorticoids. These mechanisms are complex and interrelated but are eventually mediated through influencing on the bone remodeling cycle and may result in increasing bone resorption, decreasing bone formation, but most commonly affecting both of these processes. Adding to the referred mechanisms that cause bone loss, there are background predispos-

10  Bones and Rheumatology Fig. 10.5  Risk factors for osteoporosis and fractures in inflammatory rheumatic diseases [44]

215

Background risk: • Age • Gender • Family osteoporosis • Low BMI • Fall risk • Life-style

Disease related: • Inflammation • Immobility • High Glucocorticoids dose

Predisposing Factors of Osteoporosis and Fractures in Inflammatory Rheumatic Diseases

Other factors: • Vitamin-D deficiency in SLE • Spine rigidity in AS

10.5.1.1 Role of pro-Inflammatory Cytokines • Many of the pro-inflammatory cytokines and growth factors (Fig. 10.6) [46] involved in the inflammatory processes in rheumatic diseases have been found to have a great impact on osteoclast differentiation and activation either directly, by acting on cells of the osteoclast lineage, or indirectly, by modulating the expression of the key osteoclastogenic factor (RANKL) and/or its inhibitor, OPG [47]. • Because a wide range of cytokines have positive and negative impact on OPG/RANKL system or directly on osteoclastogenesis, they are usually kept in balance in healthy subjects. However, imbalance of these cytokines occurs during inflammation but varies between disease states, and this variation would account for differences in predisposition to bone loss. • The cytokines that have positive (stimulatory) effects on osteoclastogenesis include TNF-α, IL-1b, IL-6, IL-11, and IL-17, whereas those that have negative (inhibitory) effects include 10.5.1 Effects of Systemic interferon (IFN)-γ, IL-4, and transforming Inflammation growth factor-β (TGF-β) [48]. • For instance, tumor necrosis factor-alpha Inflammatory process in rheumatic diseases is (TNF-α) can increase the expression of usually associated with skeletal destruction. RANKL by osteoblasts and hence induce The effects of inflammation in induction bone osteoclastogenesis and the bone-resorbing loss involve two mechanisms, the role of pro-­ activity. However, TNF-α and interleukin-1 inflammatory cytokines and/or the role of inflam(IL-1) can synergize with RANKL to directly matory cells. enhance bone resorption by osteoclasts. ing factors, which increase the risk of fractures due to bone loss, and they include age, gender, family history of osteoporosis, low body mass index (BMI), falling risk, and sedentary lifestyle (Fig. 10.5) [44]. The following sections will discuss the main underlying mechanisms that cause bone destruction in different rheumatic conditions, namely, the disease activity (inflammation), immobility, and treatment with glucocorticoids are considered. Noting that each rheumatic disease has a unique effect on articular bone or on other site on skeleton whether local or generalized bone loss, however, they remarkably share common pathways of skeletal remodeling (the RANKL/OPG pathway), which is involved in the regulation of bone resorption. In addition, most human and animal studies in the field of rheumatic arthritis have referred to the osteoclast as the principal cell type mediating bone loss in arthritis [45].

216

A. Abdulkhaliq Inflammatory disease

Immobility

Inflammation

Nutrition

Hypogonadism

↓ lean mass

↓ leptin/IGF-1/ estradiol



IFN-γ

TNF-α/IL1β/IL-17

TNF-α – –

DKK/1 wnt



+ RANKL



Osteoblasts bone formation –

Therapeutic glucocorticoids

Osteoblasts bone resorption +

Fig. 10.6  Illustration of the impacts of chronic inflammatory disease on bone formation and resorption. A stimulatory effect is indicated by C and an inhibitory effect by K [46]

10.5.1.2 Role of Inflammatory Cells • Under normal conditions, RANKL is derived from osteoblasts; however, during inflammation, a variety of inflammatory cells can also produce RANKL including lymphocytes and fibroblasts, which have been found in the inflamed synovium in various studies [49–51]. The expression or production of RANKL on/ from non-osteoblastic cells causes a direct osteoclastogenic effect independent of osteoblasts. • An example of these cells is T lymphocytes that are derived from Th17 subset, which has been called so after the ability of these lymphocytes to secrete IL-17, and hence they are

considered to have an osteoclastogenic cytokine profile [52]. The presence of this lymphocyte subset prominently in inflammatory arthritis could explain the tendency to local osteoclastogenesis and thus bone destruction in this condition [53]. • A subsequent to the increased bone resorption, there should be also a stimulation of bone formation because the processes of bone resorption and formation are normally tightly coupled. However, during chronic inflammation, “uncoupling” of bone formation from resorption occurs with a suppressed or decreased bone formation relative to the high degree of resorption.

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10.5.1.3 Causes of Uncoupling Process The Wnt Signaling and its Antagonist, DKK1 Studying animal models of inflammatory arthritis could explain the uncoupling process via the implication of the Wnt-signaling pathway and precisely the Wnt antagonist dickkopf-1 (DKK1), in this process [54]. The canonical Wnt-signaling pathway is essential for bone development, directing differentiation of mesenchymal precursor cells into mature osteoblasts, as well as having a major role in the normal development of the skeleton in the embryo [55, 56]. The naturally occurring soluble Wnt antagonists such as DKK1, which suppress this process, are important during nor-

mal bone remodeling. This finding has been supported by that the DKK1 knockout mice develop an increased bone mass [57] and conversely myeloma cells with aberrant DKK1 expression are associated with purely lytic lesions with little evidence of bone formation [58]. The synovial fibroblast can secrete DKK1; however, in rheumatoid arthritis, the secretion is enhanced by TNF-α, and thus the circulating levels of DKK1 have been found much elevated in those patients [54]. Thus, the secreted DKK1 from the synovium would have a suppressive effect on osteoblast maturation and on OPG function leading to inhibition of local bone formation and increased bone resorption, respectively. Understanding the mechanism of Wnt signaling and its antagonist, DKK1 (Fig.  10.7), is very important, since administration of DKK1

↑ Bone resorption ↓ Proliferation ↓ Differentiation ↓ Bone formation

Osteoblast

↓ OPG

↑ DK

K1

Osteoclast

Synovial fibroblast TNFα

Immune cell

Inflamed synovium Bone

Fig. 10.7  Schematic illustration of the possible role of DKK1 in the bone remodeling imbalance in inflammatory joint disease. Production of DKK1 in response to TNF-α production by inflammatory cells is proposed to inhibit

bone formation but increase bone resorption by osteoclasts through a suppression of OPG production by osteoblasts [46]

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antibody would be able to prevent bone erosions and reverse this block on osteoblast formation which resulted in a paradoxical excess of bone formation during inflammation as proved by the development of new osteophytes [54]. Alteration of Glucocorticoid Signaling The effects of glucocorticoids will be explained later in the following sections, but the current paragraph will discuss the influence of inflammation on glucocorticoid action in bone cells. Because of the intracellular metabolism of glucocorticoids by 11b-hydroxysteroid dehydrogenases (11β-HSDs) [59], it has become known that the levels of active glucocorticoids present within the circulation differ from that in the tissues. Specifically, 11β-HSD1 enzyme is expressed on osteoblast and can increase local glucocorticoid action in these cells by converting the inactive glucocorticoids such as cortisone and prednisone to their active counterparts’ cortisol and prednisolone, respectively. Overexpression of the enzyme in osteoblasts reduces proliferation and the synthesis of bone-­ specific proteins such as osteocalcin when cells are exposed to inactive glucocorticoids [60, 61]. It was reported previously by [62] that pro-­ inflammatory cytokines such as TNF-α or IL-1b can effectively induce the expression and activity of this enzyme in osteoblasts. Thus, during inflammation, osteoblasts at the site of bone exposed to pro-inflammatory cytokines are likely to also be exposed to high doses of locally active glucocorticoid [62, 63]. This is potentially a major mechanism by which the uncoupling process of osteoblasts and osteoclasts occurs. Overall, a high glucocorticoid level in osteoblasts will decrease bone formation through direct effects on osteoblasts [64], but it can also induce osteoclastogenesis due to upregulation of RANKL and downregulation of OPG in osteoblast precursors [42]. Studying the correlation of locally generated glucocorticoids with other proposed mechanisms of uncoupling such as DKK1 induction is essentially needed for therapeutic purposes of rheumatic diseases.

A. Abdulkhaliq

10.5.2 Effects of Immobility Immobility has consequences on all inflammatory diseases specifically neuromuscular and joint disease. The major impact on bone occurs due to uncoupling process that results in reduced bone formation and increased bone resorption [65] with overall bone loss. It has been found that osteocytes mediates mechanosensing, which means they can response to mechanical strain and maintain bony matrix via modulation of the major pathways such as the Wnt pathway that couple bone formation and resorption [66]. This effect may partly be dependent on estrogen receptor signaling, and thus hypogonadism would reduce the mechanosensing [67]. Regular exercises can maintain force on bone and thus control bone loss through mechanical stimulation. However, a more advanced approach is the administration of a vibration signal that could stimulate mechanosensing effects, which in turn will induce an anabolic response to bone [46].

10.5.3 Effects of Glucocorticoids Glucocorticoids (GCs) are frequently prescribed for patients with variety of chronic inflammatory diseases such as rheumatic diseases. An excess of circulating GCs has a major negative effects on bone [64, 68, 69]. These adverse effects on bone are owing to reduced bone formation, characterized by a low mineral apposition rate that is explained by decreased numbers of osteoblasts, while bone resorption is unchanged or even elevated [70], leading to the development of glucocorticoid-­induced osteoporosis (GIOP). Overall negative effects of GCs on bone are either directly on bone cells or indirectly by affecting the bone metabolism. The underlying molecular mechanisms of GIOP include the increased apoptosis of osteoblasts and osteocytes and increased half-life time of osteoclasts, i.e., the direct effects on bone cells (Fig. 10.8) [71]. It has been reported that the increased osteoblast apoptosis results in a significant reduction in bone formation, while decreased osteocyte num-

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Effects of Corticosteroid on Bones

Indirect Effects

Direct Effects

↓↓ Osteoblast Bone formation Via:

↑ Osteocyte Apoptosis

↓ Bone Strength

↑ Osteoblast Apoptosis

↑↑ Osteoclast Bone Resorption Via:

↑ Osteoclastogenesis ↓ Osteoclast Apoptosis

↓ Osteoblast Proliferation

↓ Bone Mass

↓ Bone Function

OSTEOPOROSIS

Fig. 10.8  The direct effects of glucocorticoids on bone [71]

bers result in a disturbed osteocyte-canalicular network and thus failure to respond to bone damage [72]. The process of apoptosis is induced by activating caspase-3 [73] and glycogen synthases kinase 3β (GSK3β), which suppresses the Wnt-signaling pathway by increasing the production of DKK-1, the Wnt pathway inhibitor [74, 75]. In addition to the increased apoptosis of osteoblasts, GCs impair osteoblast function by suppressing osteoblast differentiation [76] via interfering with both the bone morphogenetic protein (BMP) pathway and the Wnt-signaling pathway. Moreover, recent studies proposed that high doses of GCs cause a shift of bone marrow stromal cells, the precursor cells of osteoblasts, to differentiate toward adipocytes instead of osteoblasts. This is mainly achieved either through an increased expression of the peroxisome proliferator-­activated receptor-γ2 (PPR- γ2) and repression of the osteogenic transcription factor Runt-related protein 2 [77] or via suppres-

sion of AP-1, a process that not only mediates anti-­inflammatory actions but also reduces bone strength [78]. In contrast to increased apoptosis of osteoblasts and osteocytes, GCs therapy would reduce the apoptosis of osteoclasts by extending their life span through upregulation of RANKL and suppression of OPG [42]. Likewise direct effects on osteoblasts, osteocytes, and osteoclasts, GCs have indirect effects on bone (Fig.  10.9). Previous studies asserted that GCs impair bone metabolism by inhibiting both the gastrointestinal absorption and the renal tubular reabsorption of calcium, leading to hypocalcaemia and the subsequent hyperparathyroidism [71]. Recent reports referred that GCs have influenced the bone mineralization by decreasing the production of important proteins for matrix formation, namely, osteocalcin and type 1 collagen [69]. Furthermore, GCs can cause steroid myopathy [79] [4] that may increase the risk of falling and thus indirectly increase the fracture risk.

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Effects of Corticosteroid on Bones

Indirect Effects

Direct Effects

Fracture Risk Via:

Impaired Bone Metabolism Via: Bone Mineralization Via: GIT Ca+2 Absorption Urinary Ca+2 Reabsorption Urinary Ca+2 Excretion Androgens

Ca+2 Levels

PTH

Bone Resorption

Osteocalcin Type I Collagen

Risk of Falling due to Steroid Myopathy

Bone Formation

OSTEOPOROSIS

Fig. 10.9  The indirect effects of glucocorticoids on bone [71]

10.6 C  ommon Bone Diseases Associated with Rheumatic Disease Osteoporosis-related fragility fractures represent one of the most important complications that may occur in patients with rheumatic diseases; obviously, these fractures may contribute to an important decrease in quality of life, and hence osteoporosis becomes increasingly recognized as an eminent public health problem. Osteoporosis is a metabolic bone disease characterized by both low bone density (mass) and low bone quality, which includes not only microarchitecture deterioration of bone tissue but also alterations in bone remodeling, damage accumulation (e.g., microfractures), and mineralization. These changes in bone density and quality enhance bone fragility with a consequent increase in fracture risk after minimal trauma. Osteoporosis is caused by an imbalance between

bone formation and resorption with in favor of bone resorption over bone formation, leading to altered bone remodeling. The reduction in bone mass can be quantified by measurement of bone mineral density (BMD) using dual-energy x-ray absorptiometry (DXA), which is the diagnostic method of osteoporosis [80]. Therefore, osteoporosis can be defined by DXA result when T score is ≤2.5 (i.e., bone density is 2.5 standard deviation below estimated peak BMD for the population), whereas osteopenia is defined when a T score is between −1 and −2.5.

10.6.1 Rheumatoid Arthritis and Bone Loss Rheumatoid arthritis (RA) is characterized by three types of bone lesions: periarticular osteopenia, bone erosions, and osteoporosis:

10  Bones and Rheumatology

• Periarticular osteopenia is one of the first radiographic signs of RA. It appears markedly in early disease and is mainly associated with disease activity. • Bone erosions develop within the first months of the disease onset and account as the radiographic sign of RA and reflect undesirable prognosis of RA. Hence, the extent and severity of the erosions reflect the increasing disease activity and indicate the disability of the disease. Within 6  months of disease onset, less than 50% of patients showed radiographic erosions, while almost 70% of the patients have erosions detected by MRI [81–83] and may be accompanied by bone edema, where CD34+ cells and potential osteoclast precursors [84] can be found during joint aspiration. • Osteoporosis in RA is mainly characterized by marked loss of bone in the hip and the radius, while the axial bone is scarce, a pattern not similar to that of postmenopausal osteoporosis. In addition, several cross-sectional studies reported a lower bone mineral density (BMD) in patients with RA, with a twofold increase in osteoporosis compared to age- and sex-matched controls.

10.6.1.1 Predisposing Factor of Osteoporosis in RA In addition to the risk factors of osteoporosis (Fig.  10.5), other factors may also contribute in RA, such as muscle wasting, glucocorticoids therapy, and disease duration. Interaction between several factors should be considered, for example, additional muscle wasting contributes to increased immobilization [85]. 10.6.1.2 Pathological Process • Several evidences suggested the presence of osteoclasts at the site of bone erosions, indicating the increased of bone resorption [86, 87]. • In RA, the local and generalized bone loss share common pathways: the RANKL/OPG pathway. The main inflammatory cytokines

221

that have been found in RA and involve in upregulating RANKL, with subsequent activation of osteoclastogenesis, include TNF-α, IL-1, IL-6, and IL-17 [88, 89]. • The Wnt-signaling pathway is another pathway that regulates osteoblast activity, and thus the activation of the Wnt/β-catenin pathway is crucial for osteoblastic differentiation [90, 91]. There are two blockers of the Wnt-­ signaling pathway, dickkopf-1 (Dkk-1) and sclerostin, both of which play an important role in the pathogenesis of RA.  TNF-α can induce both sclerostin and Dkk-1 [89], leading to inhibition of osteoblastic differentiation. • Further studies in RA patients confirmed these pathological processes and revealed that OPG/ RANKL ratio was lower than in healthy controls, while Dkk-1 and sclerostin were higher. After treatment with anti-IL-6, OPG/RANKL increased, Dkk-1 decreased, and sclerostin increased [92].

10.6.1.3 M  anagement of Bone Loss in RA • Recent treatments with biological agents were introduced in patients with rheumatoid arthritis. All available TNF-alpha blocking agents are quite successful in the prevention of erosion formation. • However, progression of structural damage in RA patients treated with methotrexate can be avoided by denosumab, a fully human monoclonal IgG2 antibody that binds RANKL [93]. • It has also been found that in patients with RA treated with infliximab, the bone loss was abolished in the spine and hip, but not in the metacarpal cortical hand [94]. • Moreover, preventing the loss of vertebral strength in patients with RA can be principally achieved by treatment with alendronate [95]. • After this extensive review, here comes the value of early diagnosis of RA and early and aggressive intervention with disease-­ modifying anti-rheumatic drugs (DMARDs) to prevent bone destruction, osteoporosis, and erosions.

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10.6.2 Systemic Lupus Erythematosus and Bone Loss 10.6.2.1 P  redisposing Factors of Bone Loss in SLE • In addition to the traditional background factors, there are also disease-related factors (Fig.  10.5) such as inflammation, metabolic factors, hormonal factors, serologic factors, and medication-induced adverse effects [96]. • Another factor that may contribute in decreased BMD in SLE is the associated high frequency of vitamin D deficiency [97–99], a metabolic condition that induces bone loss. Vitamin D deficiency might induce bone loss in SLE via several factors including (a) photosensitivity (so patients avoid exposure to the sun and use sunscreens), (b) dark skin pigment, (c) renal failure, and (d) treatment with GC (has a dual action, it can induce bone loss, but also it has a beneficial effect on bone mass by suppressing inflammation) and possibly hydroxychloroquine (HCQ) (via inhibiting hydroxylase α1 that form active vitamin D), which showed a controversial results [98, 100]. Due to these inconsistent results of HCQ, further studies in large groups of SLE patients and patients with other diseases treated with HCQ are needed to clarify the relationship between HCQ uses and bone metabolism. • Changes in hormonal pattern may also negatively influence the BMD in patients with SLE, where a relatively high estrogenic and low androgenic state and a decrease in dehydroepiandrosterone (DHEA) have been demonstrated and associated with low BMD [101]. • Collectively, the factors that may adversely affect bone mass, resulting in osteoporosis and possible fracture risk in SLE, have been summarized in Table 10.1. 10.6.2.2 Pathological Process • Chronic systemic inflammation is a cause of bone loss in SLE, where the activated inflammatory cells at sites of inflammation produce a wide spectrum of cytokines that stimulate local and generalized bone resorption.

A. Abdulkhaliq Table 10.1  Summary of risk factors for osteoporosis in patients with SLE [101] Risk factors for osteoporosis in patients with SLE Non-modifiable risk factors  • Caucasian or Asian ethnicity.  • Female sex.  • Advanced age.  • Personal or family history of osteoporotic fractures.  • High risk of falls.  • Premature menopause. Modifiable risk factors  • Weight 3 months duration ACR 2010 recommendations on counseling for lifestyle modification  • Weight-bearing activities  • Smoking cessation  • Avoidance of excessive alcohol intake (>2 drinks per day).  • Nutritional counseling on calcium and vitamin D intake.  • Fall risk assessment .  • Baseline dual x-ray absorptiometry .  • Serum 25-hydroxyvitamin D level .  • Baseline height .  • Assessment of prevalent fragility fractures .  • Consider radiographic imaging of the spine or vertebral fracture assessment for those initiating or currently receiving prednisone 5 mg/day or its equivalent.  • Calcium intake (supplement plus oral intake) 1200–1500 mg/daya.  • Vitamin D supplementationa. Recommendations for calcium and vitamin D supplementation are for any dose or duration of glucocorticoids, rather than a duration of 3 months

a

10.6.3 Ankylosing Spondylitis and Bone Loss Inflammation in ankylosing spondylitis (AS) is characterized by subchondral bone marrow edema with subchondral bone erosive lesions and eventually to subchondral new bone formation through the articular cartilage and ossification of the periarticular ligaments [85]. Bone edema is accounted as a sign of inflammatory activity and may affect limited or extensive parts of vertebrae (Fig.  10.10). Recent studies suggested a possible sequence of events of new bone formation in AS, as follows: first erosions at the site of inflammation, followed by repair reaction, and subsequently ended by new bone formation (10). • For instance, at the corners of the vertebral bodies, there might be marginal erosive lesions with adjacent subchondral edema and sclerosis (Romanus lesion). Also, a new periosteal intraosseous bone formation was found and provided the typical picture of squaring of the vertebrae [85].

224 Fig. 10.10  Sites of bone edema, bone loss, and bone erosion in AS [85]

A. Abdulkhaliq

Bone edema

Bone loss

Erosions: Anderson sign

Periosteal

Romanus sign Interapophyseal

10.6.3.1 Fracture Risk in AS Subsequent results to bone changes in AS lead to an increase in bone loss (osteoporosis) and bone fragility and therefore increased the risk of bone fractures. • AS is associated with an elevated risk of vertebral fractures, which are six to seven times higher than in healthy population [117, 118], and these fractures are often accompanied by neurological signs and symptoms [119]. However, the increased in morphometric and clinical vertebral fractures [120] but not in peripheral (forearm or hip) fractures indicates a more local effect of AS on bone, unlike RA, where the inflammatory effects are more systemic. Furthermore, despite sharing similar pathogenesis of osteoporosis but with different clinical phenotypes, bone loss in AS is accompanied by new bone formation contrasting to RA and postmenopausal conditions, • Of most important types of spinal fractures in AS includes wedging fracture, which contributes to spine rigidity and hyperkyphosis of upper part of the spine and impaired physical function [119, 121, 122]. In addition to wedg-

ing fracture, structural damage of the spine and the disease activity are other significant contributors to hyperkyphosis [123].

10.6.3.2 M  anagement of Bone Loss in AS • Because of the concomitant bone loss and the new abnormal bone formation and the presence of syndesmophytes, the reliability of BMD measurement is affected, and there would be a large variation in the prevalence of osteoporosis in patients with AS [124, 125]. • Taken together, AS is characterized by bone and cartilage degradation. The bone destruction reflects the systemic inflammatory effects on bone density and can be inhibited by TNF-α blocking agent. However, the cartilage damage might be related to syndesmophyte formation, which is not influenced by anti-­ inflammatory therapy [120]. This highlights the suggestion that bone degradation and new bone formation are uncoupled mechanisms in AS, the reason that might make their therapeutic intervention basically different. • A remarkable but yet not confirmed finding has shown that the risk of clinical fracture

10  Bones and Rheumatology

decreased in AS patients taking NSAIDs, which could relieve the inflammatory back pain and stiffness and thus improving the physical activity that helped in maintaining bone mass and reducing the risk of falling and subsequent fracture [126, 127]. In addition, it has recently been suggested that NSAIDs may also inhibit the formation and growth of syndesmophytes of AS in the spine via interfering with the prostaglandin metabolism. Therefore, if the divergent inhibitory effects of NSAIDs on osteoporotic fractures (bone loss) and progression of syndesmophytes (bone formation) can be confirmed, this would be an important clue in further explaining pathophysiological mechanisms in AS. • In contrast to the treatment of osteoporosis in patients with RA, treatment of osteoporosis in patients with AS is not yet common. Data supporting the efficacy of this treatment in AS are rare. Of all bisphosphonates, alendronate and risedronate are found to be effective in increasing BMD in men. Alendronate and risedronate significantly increase BMD in both vertebrae and femur, with a significant reduction of vertebral fractures [128, 129]. More recently teriparatide was tested with the same aims, but only a positive effect on BMD could be shown [130]. It is clear that there is a need for evidence-­based knowledge in these fields in the near future. Our studies highlight the need to develop strategies to identify high-risk patients with AS. Research on the treatment of osteoporosis to prevent vertebral fractures in these patients is urgently needed.

10.6.4 Glucocorticoid-Induced Osteoporosis (GIOP) Steroids are widely used in the medical practice to treat various diseases such as asthma, systemic connective tissue diseases, and other autoimmune diseases and in addition to rheumatic diseases. Treatment with GCs results in bone loss

225

within 1 month after initiation of the therapy but primarily occurs in the trabecular bone, so that it mainly increases the risk of vertebral fracture rather than non-vertebral fractures [79]. Fractures are considered the most clinically relevant risk of prolonged steroid therapy. GIOP is a common type of secondary osteoporosis which occurs at any age and in both men and women. It has been known that one loss in GIOP is biphasic, with a rapid reduction in BMD of 6–12%* which occurs followed by a slower annual loss of about 3%* for as long as the glucocorticoids are administered [131, 132].

10.6.4.1 Impact of GIOP • As a consequent to the bone loss during GCs therapy, it has been reported that the relative fracture risk within the first 3 months after initiation of the therapy increases by 75% even before any BMD changes occur [133]. • Although the increase of fracture risk has appeared to be dose dependent [134], it was found to be partially reversible so that the fracture risk would gradually return to baseline [135]. 10.6.4.2 Approaching Managements of Patients with GIOP • American College of Rheumatology (ACR) have developed and updated recommendations to provide guidance for prevention and treatment of GIOP in order to be applied by the physicians in light of each patient’s circumstances. • ACR recommendation 2001 [136] has been updated and replaced by ACR recommendation 2010 [137], which had expanded the recommendations for counseling (Table  10.2) and monitoring updated pharmacological guidelines and used patient’s overall clinical risk instead of T score alone. –– Afterward, ACR 2017 recommendations have been released for GIOP prevention and treatment, based on the balance of relative benefits and harms of the treatment options and highly considering the quality

226

of the evidence and patients’ values and preferences [138]. Therefore, due to limited evidence on the benefits and harms of interventions in GC users, most recommendations in ACR 2017 guidelines are conditional or of good clinical practice. The strength of the recommendations is based on the fracture risk categories in GC-treated patients [138]. –– The ACR 2017 recommendations for GIOP prevention and treatment have addressed, in addition to all adults’ categories (< 40 years and > 40 years of age), special populations categories, namely children, people with organ transplants, women of childbearing potential, and people receiving very highdose GC treatment. –– The initial approach of patients with GIOP begins with clinical assessment of fracture risk by interpreting detailed clinical and biochemical data, together with identifying the diagnostic criteria for assessment of bone mineral density (BMD) results, as follows: 1. Clinical Assessment: This is concerned with having detailed medical history to identify the cumulative risk factors for bone loss (Fig.  10.11) and performing proper physical examination to detect any underlying medical conditions or evidence of osteoporosis such as fracture, kyphosis, and loss of height or determine muscle strength and size. 2 . Biochemical Assessment: The baseline levels of the following parameters are needed to be obtained in order to rule out any underlying medical diseases that may affect the outcome of GIOP such as low levels of calcium or vitamin D; those would affect the bone formation and metabolism [137, 138]. These parameters include: • Complete blood cell count. • Serum calcium and phosphorus. • Serum 25-hydroxyvitamin D. • Serum-free testosterone in males. • Estradiol in premenopausal women. • Renal Function Tests specifically 24-hour urinary calcium and sodium. • Liver function test, because healthy liver is important for synthesis of sex hormones.

A. Abdulkhaliq

3. Assessment of Bone Mineral Density (BMD): Measuring the BMD is one of the salient determinants of bone strength. It can be measured at different sites in the body by distinct methods. For instance, dual-energy x-ray absorptiometry (DXA) measures BMD mainly at lumbar spine and proximal femur, while quantitative computed tomography (QCT) is used mostly to estimate bone density at the forearm, tibia, or lumbar spine. The World Health Organization (WHO) has defined the diagnostic criteria for assessment of BMD results (Table 10.3) [139]. 4. Assessment and Classification of Fracture Risk: Identifying patients with increased fracture risk solely using BMD assessment has some limitations due to its age dependency and its inaccuracy in measuring bone quality. Therefore, it has been recommended that fracture risk should be assessed using tools that calculate the absolute fracture risk for a given patient. One of the available tools proposed by the World Health Organization (WHO) is called Fracture Risk Assessment (FRAX) tool [140]. FRAX is a unique model that is considered in calculating the risk of the following factors, age, sex, race, family history, the BMD, and the usage of BMD, but excludes the dosage and the evaluation of the risk factors of falls and the presence or absence of prevalent vertebral deformities, although they are known as risk factors for fractures. The output of FRAX calculation is a 10-year probability of hip fracture and the 10-year probability of a major osteoporotic fracture (clinical spine, forearm, hip, or shoulder fracture) [140]. • Based on the risk factors shown in Fig.  10.11 as well as the FRAX results, adult patients receiving GC can be classified into low-, moderate-, and high-risk categories accordingly (Fig.  10.12). The ACR 2017 recommendations for GIOP prevention and treatment have addressed, in addition to all adults’ categories (< 40 years and > 40 years of age), special populations, namely children, people with organ transplants, women of childbearing potential, and people receiving very high-dose GC treatment.

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Fig. 10.11  Risk factors that may shift an individual to a greater risk category for GIOP (ACR 2010) [137] Table 10.3  WHO criteria for assessment of BMD [139]

• Therefore, the primary implication of ACR 2017 recommendation is to clarify that all clinicians treating patients with GCs have to be aware of the GIOP risk, identify patients at high fracture risk (Fig.  10.12),

and be able to provide the appropriate treatment [138]. • Moreover, the assessment of fracture risk may not only be useful in treatment decisions, but also in improving patients’ treat-

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Fig. 10.12  Fracture risk categories in GC-treated patients [138]

ment compliance that would provide the patients a better insight into their future fracture risk.

10.6.4.3 Recommendations for Fracture Risk Assessment and Reassessment of Patient with GIOP These recommendations are considered as good practice recommendations. • Initial fracture risk assessment: For all adults and children, an initial clinical fracture assessment should be performed as soon within six months of the initiation of long-term GC treatment. This clinical assessment should include the following: –– A detailed clinical history of GC use (dose, duration, mode, and pattern of use), –– An evaluation of underlying risk factors for fracture including history of falls, fractures, frailty, others such as (malnutrition, significant weight loss or low body weight,

hypogonadism, secondary hyperparathyroidism, thyroid disease, family history of hip fracture, history of alcohol use [at > 3 units/day] or smoking), and other clinical comorbidities. –– A physical examination including measurement of weight and height, detailed examination of musculoskeletal system, and other clinical findings of undiagnosed fracture (e.g., spinal tenderness, deformity, and reduced space between lower ribs and upper pelvis). For adults >40 years old, the initial absolute fracture risk should be evaluated using FRAX with correction of GC dose and BMD (if available) as prompt as possible but within at least six months of starting the GC therapy (Fig. 10.13) [138]. For adults 40 years old but not of childbearing potential, and men >40 years old, who are at moderate to high risk of fracture (Fig. 10.15). –– Adults 6 months at a dose of >7.5 mg/day), who have either a hip or spine BMD with Z score 10%/year at the hip or spine (Fig. 10.15). –– Special populations that have further subgroups including (Table 10.4): Women who meet criteria for moderateto-high risk of fracture and are of childbearing potential but do not plan to become pregnant within the period of OP treatment and are using effective birth control or are not sexually active.

Adults >30 years of age who are receiving very high-dose GC treatment (initial prednisone dose of >30 mg/day [or equivalent GC exposure] and a cumulative annual dose of >5  gm) (Table 3 of main reference). Adults who have received an organ transplant and who are continuing treatment with GCs. GC-treated children at 4–17 years of age are further subdivided into two groups (Table 10.4).

10.6.4.5 Rationale of Pharmacotherapy of GIOP • GIOP can be partially prevented by using bisphosphonates (alendronate and zoledronic acid) [142]. However, oral bisphosphonates are limited by low adherence rates, and therefore zoledronic acid provides the intravenous form of this medication and can be prescribed rather than the patient receiving no additional therapy beyond calcium and vitamin D. • On the other hand, PTH 1-34 (teriparatide) therapy seems to be superior to oral bisphos-

10  Bones and Rheumatology

231

Fig. 10.15  Initial pharmacologic treatment for adults [138]. Recommended doses of calcium and vitamin D are 1000–1200  mg/day and 600–800  IU/day (serum level ≥20 ng/mL), respectively. Lifestyle modifications include a balanced diet, maintaining weight in the recommended range, smoking cessation, regular weight-bearing and resistance training exercise, and limiting alcohol intake to 1–2 alcoholic beverages/day. Very high-dose glucocorti-

coid (GC) treatment was defined as treatment with prednisone ≥30 mg/day and a cumulative dose of >5 gm in the past year. The risk of major osteoporotic (OP) fracture calculated with the FRAX tool should be increased by 1.15, and the risk of hip fracture by 1.2, if the prednisone dose is .7.5 mg/day (e.g., if the calculated hip fracture risk is 2.0%, increase to 2.4%)

phonates but is more expensive [143] and can be used if bisphosphonate is not appropriate. • If neither oral nor IV bisphosphonates nor teriparatide treatment is appropriate, denosumab should be used rather than the patient receiving no additional treatment beyond calcium and vitamin D. Denosumab is a humanized monoclonal antibody to RANKL and is useful for GC-treated patients with renal insult but with stable serum Ca+2 levels and are not candidates for bisphosphonates or teriparatide. Denosumab has been approved for the prevention of vertebral and non-vertebral fractures, in women with postmenopausal osteoporosis [144]. Moreover, it was revealed that

denosumab therapy increased spine and hip BMD and reduced bone turnover markers for 12  months in patients received GC [145]. A recent randomized, doubleblind, comparative study of denosumab and risedronate in patients ≥19 years of age taking prednisolone ≥7.5 mg/ day for ≥3 months reported that denosumab significantly increased spine and femoral BMD compared to risedronate [146]. • If none of these medications is appropriate for postmenopausal women, raloxifene [selective estrogen receptor modulator (SERM)] should be used rather than the patient receiving no additional treatment beyond calcium and vitamin D. The order of the preferred treatments

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Table 10.4  Recommendations for initial treatment for prevention of GIOP in special populations of patients beginning long-term GC therapy [138] Recommendations for initial treatment for prevention of GIOP in special populations Women of childbearing potential at moderate-to-high risk of fracture who do not plan to become pregnant within the period of OP treatment and are using effective birth control or are not sexually active     Treat with an oral bisphosphonate over calcium and vitamin D alone, teriparatide, IV bisphosphonates, or denosumab.     Oral bisphosphonates preferred for safety, cost, and because of lack of evidence of superior antifracture benefits from other OP medications.     Other therapies if oral bisphosphonates are not appropriate, in order of preference:       Teriparatide         Safety, cost, and burden of therapy with daily injections     Consider the following therapies only for high-risk patients due to lack of safety data on use of these agents during pregnancy:       IV bisphosphonates         Potential fetal risks of IV infusion during pregnancy       Denosumab         Potential fetal risks during pregnancy     Conditional recommendations because of indirect and very low-quality evidence on benefits and harms of these treatments to the fetus during pregnancy Adults age ≥30 years receiving very high-dose GCs (initial dose of prednisone ≥30 mg/day and cumulative dose >5 gm in 1 year)     Treat with an oral bisphosphonate over calcium and vitamin D alone.     Treat with an oral bisphosphonate over IV bisphosphonates, teriparatide, or denosumab.     Oral bisphosphonates preferred for safety, cost, and because of lack of evidence of additional anti-fracture benefits from other OP medications.     If bisphosphonate treatment is not appropriate, alternative treatments are listed by age (≥40 years and 38.3 on several occasions. • Duration ≥3 weeks. • No clear diagnosis after 1 week of in-hospital investigation.

11.2.2 Epidemiology The epidemiology of FUO has changed over time due to scientific and technologic advances (better imaging, more advanced organism isolation, and more understanding of connective tissue disease). A prospective multicenter study on fever of unknown origin showed the following distribution: connective tissue diseases 22%, infection 16%, malignancy 7%, miscellaneous 4%, no diagnosis 51%.

Box 11.1 Initial evaluation for FUO

• Comprehensive History (Table 11.2) • Detailed Physical examination (Table 11.2) • CBC with differential & Blood film • U&E–LFTs–LDH–ESR - CRP • hepatitis A, B, and C serologies if LFTs are abnormal • Blood cultures (X3  - different sites  several hours between each set  - off antibiotics) • HIV antibody assay and HIV viral load for patients at high risk • Urinalysis + microscopic examination + urine culture • CXR

Epidemiology: Table  11.1 shows the etiologies of FUO.

M. Cheikh and N. Bahabri

11.2.3 General Principles in the Treatment of FUO (Table 11.2) Physician should explain to the patient that FUO is a well-known entity, and it needs time for investigation to decrease anxiety of the patient. Empiric therapy with antimicrobial or glucocorticoids should not be given to stable patients with FUO because it often obscure or delay the diagnosis [29]: • The diagnostic yield of some investigation like cultures will be reduced after starting antimicrobial. • Empiric treatment of a certain infection can affect other infection (e.g., therapeutic trial for tuberculosis with rifampicin may suppress staphylococcal osteomyelitis or diminish the ability to detect difficult to isolate organisms causing endocarditis. • The duration of a therapeutic trial is also unclear. • Initiation of glucocorticoid without rolling out infection can lead to severe life-threatening infections. There are some exceptions where patient with FUO should be treated empirically. The exceptions are: 1. Septic or hemodynamically unstable patient → empirical treatment. 2. Immunocompromised or neutropenic patient→ empirical treatment. 3. Query giant cell arteritis → treat with corticosteroids until biopsy result → risk of visual loss. Figure 11.1 shows a suggested algorithm to approach a patient with FUO.

11  Fever and Rheumatology

243

Table 11.1  Etiologies of FUO [1–27] Infection

Connective tissue disease

Malignancy

Miscellaneous

• Tuberculosis: require high clinical suspicion as patient can have normal PPD or interferon gamma release assay and may require biopsy to yield diagnosis. • Abscesses: Intra-abdominal, pelvic, dental, or paraspinal. • Osteomyelitis: some sites can have no localized symptoms like vertebral and mandibular osteomyelitis. • Endocarditis: consider culture negative organism→ HACK, Coxiella, Bartonella, T. whipplei, Brucella, Mycoplasma, Chlamydia, Histoplasma, and Legionella. • Other causes: Brucellosis, HIV, sinusitis, CMV, EBV, secondary syphilis, Lyme disease, prostatitis, visceral leishmaniasis, Q fever, leptospirosis, psittacosis, tularemia, melioidosis, disseminated gonococcemia, chronic meningococcemia, Whipple’s disease, and yersiniosis. • Adult Still’s disease: evanescent rash, arthritis, lymphadenopathy, and high ferritin. • Giant cell arteritis: >50y, headache, scalp pain, visual disturbances, myalgias, arthralgias, high ESR. • Other: polyarteritis nodosa, granulomatosis with polyangiitis, RA, SLE, psoriatic or reactive arthritis, PMR, Takayasu’s arteritis, mixed cryoglobulinemia. • Lymphoma (especially non-Hodgkin’s). • Leukemia. • Myelodysplasia. • Renal cell carcinoma (increase HCT, microscopic hematuria). • Hepatocellular carcinoma or other tumors metastatic to the liver. • Multiple myeloma. • Pancreatic and colon cancers, sarcomas, mastocytosis. • Atrial myxomas (arthralgias, emboli, and hypergammaglobulinemia). • Drug-induced fever. • DVT/PE. • Hematoma. • Thyroid storm, thyroiditis, adrenal insufficiency, pheochromocytoma. • Sarcoidosis. • Alcohol or granulomatous hepatitis. • Hereditary periodic fever syndromes: FMF, TRAPS, hyper-IgD syndrome, muckle-Wells syndrome, and familial cold autoinflammatory syndrome.

Table 11.2  Initial evaluation for FUO History Carefl and through history including:   • Any localizing symptoms.   • Travel Hx (TB, malaria, hepatitis, typhoid fever, parasitic infections, Rocky Mountain spotted fever, or Lyme disease).   • Exposure to TB patient.   • Unpasteurized milk and cheese,   • Animal and insect exposure.   • Immunosuppression (medication or diseases).   • Sexual contacts.   • New unusual activity.   • Drug and toxin history including alcohol, illicit drug use, over-the-counter medications and recent antimicrobial.   • Ethnic background.

Physical examination Complete physical examination including:   • Skin, mucous membranes, and lymphatic system.   • Abdominal palpation for masses or organomegaly.   • Joint examination and the back → Pott’s disease.   • Heart auscultation → new murmur (infective endocarditis).   • Sinuses.   • Prostate examination.

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Establish the diagnosis of FUO 1- Temp > 38.3 → Use fever chart to document fever 2- Duration ≥ 3 weeks 3- No clear diagnosis after Initial evaluation (see box1)

Meeting the definition

FUO

Drug Fever

Discontinue all unnnecesary Medicationfor 72 H

Fever Resolves

Fever persist

CT Abdomen & Pelvis with IV & oral contrast +



Guided Investigation

Extensive workup according to the most likely etiology

Infection

MALIGNANCY

CTD

Miscellaneous

Evaluate for IE (Modified Duke Criteria +/- TTE or TEE)



ANA



Stool occult blood



TFT



RF, anti-CCP



Tumor markers



Doppler Ultrasound



AFB stain & culture (x3)



C3, C4



CT Chest\Mammogram



Other appropriate



PPD skin test or interferon



Ferritin



EGD\Colonoscopy

gamma release assay



CK



Serum protein



Lumbar puncture



Temporal



VDRL





artery biopsy

electrophoresis 

Nuclear imaging

CMV IgM antibodies



PET scan



Heterophile Antibody



Biopsy



Brucella titer



Q fever serology



Sinus Film



Head\spine imaging



Nuclear Imaging



WBC scan



Biopsy

Fig. 11.1  Suggested algorithm to approach patient with FUO

diagnostic test

11  Fever and Rheumatology

11.2.4 Tips in FUO • Think of uncommon presentations of common diseases rather than thinking of uncommon diseases. • rheumatological > malignancy. • >40 Y → Infection > Malignancy > Rheumatological. • Rheumatological disease usually present in stable condition. • Empirical treatment not recommended unless there is an indication. • If empiric treatment is a must avoid quinolone (TB resistance). • Chills, rigors, night sweat (infection > rheumatological). • Most of undiagnosed cases of FUO are related to viruses that we don’t usually investigate. • Viral infections can give a temperature up to 40–41 °C and can persist up to 3 weeks (average 9 days).

11.3 Fever and Rheumatology 11.3.1 Introduction Approach to fever is a very challenging in a patient with rheumatic disease as it could be an infection, disease activity, or medication side effect. Fever that is thought to be due to active disease is seen in over 50% of patients with SLE [30]. On the other hand, fever is a rare presentation of RA disease activity. Infections are often difficult to diagnose and treat in this group of patient because of the following reasons: 1. Clinical manifestations of infections are often indistinguishable from the underlying disease and vice versa [52–55].

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2. The typical signs and symptoms of infection may be absent because of concomitant immunosuppressive therapies [56–58]. 3. The anti-inflammatory and antipyretic effects of glucocorticoids may diminish the usual systemic and localizing signs of infection. 4. With the immunosuppressive impact of the medication and the disease itself, the spectrum of potential pathogens is large, making empiric treatment difficult. In patient with rheumatoid arthritis, bone and joints, skin, soft tissues, and the respiratory tract are the most frequently involved sites in infectious processes [33]. In patients with chronic inflammatory rheumatic or autoimmune diseases without arthritis, infections of the respiratory tract are the most common site. Finally, ascribing fever to the underlying rheumatological disease itself in an immunosuppressed patient should be done only after reasonable and good efforts have been made to exclude infection. Figure 11.2 shows suggested algorithm to approach a patient with rheumatic disorder presenting with fever. Risk factors for infection in a patient with rheumatic disease include: • • • • • • • •

Active disease. Long-term disease damage. Neutropenia. Lymphopenia. Hypocomplementemia. Renal involvement. Neuropsychiatric manifestations. Use of glucocorticoids and other immunosuppressive drugs. • Arthrocentesis [23].

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Infection • • • • • •

Initial Work up

Drug

Disease activity

Complete history & physical exam CXR Basic work up Blood culture and other cultures as clinically indicated CRP, ESR, Procalcitonin, complement level See Table 11.3. Any positive findings pursue aggressively some examples:

History • Unexplained Headache personality changes Confusion

Abnormal CXR (table 2)

Physical Examination

• Focal Neurologic finding

Brain MRI\CT \ LP and send for: Cell count & differential Gram stain & culture AFB stain & culture Total protein, glucose, LDH Complement level SEE (table 3 CNS) • Inflamed Joint • Acute joint pain, swelling Arthrocentesis and send for: Synovial fluid for cell count Gram stain & cultures CT/MRI  especially hip and • Cutaneous lesion sacroiliac joints

Suggestive of pneumonia

Not suggestive for pneumonia

Treat

Unstable Patient

Treat empirically

Not responding

Sputum induction for TB & PCP Negative

Pleural Effusion

Thoracentesis and send for: Total protien, LDH, glucose, PH cell count & diff gramstain & culture AFB stain, TB PCR & culture ADA

Bronchoscopy + Bronchoalveolar lavage +/- Biopsy

Biopsy  Send for histology & cultures (special strains of bacteria, Mycobacteria, fungi)

Fig. 11.2  Suggested algorithm to approach a patient with rheumatic disorder presenting with fever

Points to consider in the approach to this group of patients: • Respiratory viral infections are the most common cause of fever in rheumatological patient as non-rheumatological patient. • There is no single clinical or laboratory finding that can differentiate between infection, disease activity, or drug-induced insult as a cause of

fever. It is rather a collective clinical and laboratory finding with good clinical judgment. • One of the crucial points in determining the cause of fever is to know the patient’s disease activity statues prior to presentation and if he is on immunosuppressive therapy or no. • Both the patient’s underlying rheumatic disease and its therapy need to be taken into con-

11  Fever and Rheumatology

sideration when evaluating the white blood cell count in a febrile immunosuppressed patient because: –– Glucocorticoids therapy can cause a neutrophilic leukocytosis. –– Cytotoxic drug therapy can impair a patient’s ability to mount a neutrophilic leukocytosis in response to infection. –– Neutrophilic leukocytosis may be a manifestation of certain rheumatic diseases, such as active granulomatosis with polyangiitis [101]. • Recent systemic review and meta-analysis for the utility of procalcitonin as a diagnostic marker for bacterial infection in patients with autoimmune disease showed that: –– Procalcitonin has higher diagnostic value than CRP for the detection of bacterial sepsis in patients with autoimmune disease, and the test for procalcitonin is more specific than sensitive 32. –– Procalcitonin test is not recommended to be used in isolation as a rule-out tool 32.

11.4 Fever in Rheumatology Patient 11.4.1 History Careful and through history including: • Medication history → immunosuppressed (type and for how long)→ suspect new ­infection, particular if other signs of active disease have begun to remit. • Onset of symptoms → few days → infection. • Days to weeks → disease activity/opportunistic infection • Fever pattern → episodic → disease activity/ infection.

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• Sustained → drug/CNS involvement • Shaking chills occurred in significantly more patients with proven infections (68% versus 27% non-infectious). • Contact with children (viral infection). • Recent travel and exposure to TB. • Vaccination history.

11.4.2 Physical Examination (Table 11.3) Complete physical examination includes: • Oral mucosal candidiasis →significant immunodeficiency → increased risk of opportunistic infections, such as PCP [36]. • Erythematous necrotic cutaneous lesions→? Gram-negative sepsis, in particular P. aeruginosa. • Cutaneous vesicular rash → varicella. • Pulmonary infiltrates + cutaneous lesions→? Disseminated histoplasmosis, Cryptococcus, and nocardiosis (Table 11.4). • Pulmonary infiltrates + focal neurologic deficits→? Disseminated infection with ­mycobacteria, fungi (C. neoformans, Aspergillus spp.), or Nocardia spp. (Table 11.5). • A detailed neurologic examination should be performed and repeated frequently to monitor the patient’s progress. • Each patient should undergo a careful ophthalmologic examination looking for papilledema, signs of retinal and choroid infection (e.g., cryptococcosis, toxoplasmosis), and proptosis (suggestive of orbital infection or cavernous sinus involvement). • Parotid gland enlargement → mumps. [39–57, 59–99].

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Table 11.3  Possible pathogens by the predominant immune system defect caused by pharmacological agent used in the treatment of rheumatic disease [37–38] Abnormality Qualitative defect of phagocytic function Or neutropenia

Defective cell-­ mediated immunity

Agent Corticosteroids Cyclophosphamide and other alkylating agents Azathioprine

Corticosteroids Cyclophosphamide Other alkylating agents Azathioprine Methotrexate Cyclosporine A

Infection Bacterial

Viral Fungal Bacterial

Viral Fungal

Parasites Defective humoral immunity and asplenia

Cyclophosphamide Corticosteroids (high dose) Azathioprine

Bacterial

Viral Parasites

11.5 Rheumatologic Manifestation of Infectious Diseases 11.5.1 Introduction Rheumatologic manifestations of infectious diseases are well-recognized and relatively common. This topic will review the most common infectious diseases associated with rheumatologic manifestations. An overview of each infectious agent is presented separately.

11.5.1.1 H  epatitis B Virus Arthritis [104] Evidences have shown that four rheumatologic syndromes are linked with hepatitis B virus infection.

Gram positive Coag (−) staph, Staphylococcus aureus, Streptococcal spp., Corynebacterium spp., Bacillus spp., Nocardia spp. Gram negative Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa VZV, HSV1&2, CMV Candida spp., Aspergillus spp. Salmonella spp., Campylobacter, Listeria, Yersinia, Legionella, Rhodococcus, Nocardia, TB, non-TB Mycobacterium spp. CMV, EPV, VZV, HSV, JC virus, BK virus Candida, Histo, crypto, Coccidio, Aspergillus, pneumocystis, Zygomycetes spp., and other mold Toxoplasma, Cryptosporidium, Isospora, Microsporidia, Babesia, Strongyloides Encapsulated bacteria: Streptococcus pneumoniae Haemophilus influenzae Neisseria meningitidis Other bacteria: E. coli And GNRs VZV, Echovirus, Enterovirus Babesia, Giardia

Clinical and laboratory features of each syndrome will be described below.

11.5.1.2 A  cute Hepatitis B and Arthritis The symptoms are abrupt in onset, and they are composed of low-grade fever, a symmetrical polyarthritis which might be additive or migratory in pattern, morning stiffness, and other constitutional symptoms. The most common joints involved are the knees and small joints of the hands, but any peripheral joint might be involved with either arthralgia or frank arthritis. It may last from several days to several months. 11.5.1.3 Chronic Active Hepatitis B Chronic active hepatitis is linked with joint discomfort and occasional rash. The joints

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Table 11.4  Causes of CXR abnormalities in patient with rheumatic diseasea Radiographic pattern Localized infiltrates

Diffuse infiltrates

Nodules or nodular infiltrates

Infectious causes Bacterial pneumonia (including Legionella spp.) Mycobacteria spp. Opportunistic fungi: Aspergillus spp. Histoplasma capsulatum Coccidioides immitis Cryptococcus neoformans Pneumocystis jiroveci (uncommon) Pneumocystis jiroveci Bacterial pneumonia (haematogenous spread) Mycoplasma pneumoniae Chlamydia spp. Mycobacteria spp. (miliary pattern) Opportunistic fungi Viral Influenzae Cytomegalovirus Varicella-zoster virus (rare)

Septic emboli Staphylococcus aureus Pseudomonas aeruginosa Mycobacteria spp. Nocardia spp. Opportunistic fungi

Noninfectious causes Granulomatosis with polyangiitis Eosinophilic granulomatosis with polyangiitis Pulmonary embolus

Systemic lupus erythematosus Rheumatoid arthritis Microscopic polyangiitis Granulomatosis with polyangiitis Eosinophilic granulomatosis with polyangiitis Scleroderma Sjogren’s syndrome Dermatomyositis/polymyositis Pulmonary edema Drug induced Methotrexate Cyclophosphamide (rare) Azathioprine (rare) Granulomatosis with polyangiitis Eosinophilic granulomatosis with polyangiitis Rheumatoid arthritis Lymphoma

The appearance or progression of pulmonary disease following the initiation or intensification of immunosuppressive therapy should always prompt a thorough evaluation for a possible infectious cause

a

Table 11.5  Infections in rheumatological patient and most common causes [34, 35, 100, 102, 103, 133–136] Disease Pneumonia

Causes   • Immunocompromised patient are prone to the same pathogens acquired in the community by immunocompetent hosts.   • (S. pneumoniae, S. aureus, and enteric GNRs) are the most common isolated pathogens   • Less common organism. Fungi (Pneumocystis jirovecii→most common OI, Aspergillus spp., C. neoformans, C. immitis, and H. capsulatum) TB & non-TB mycobacteria Nocardia spp. CMV HSV

Comments   • Pneumonia is one of the most frequent life-threatening infections in patients with rheumatic diseases.   • Pneumonia in immunosuppressed rheumatic patient is a challenging diagnosis because of:    1. Pulmonary manifestations of certain rheumatic diseases and medications used to treat rheumatic diseases may produce many of the same clinical and radiographic abnormalities as pneumonia.    2. The usual radiographic appearance of pulmonary infections can be dramatically altered by immunosuppressive therapy. (continued)

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Table 11.5 (continued) Disease CNS Involvement

Causes Clinical syndrome

Non-­infectious causes NSAIDS Azathioprine IVIG Sarcoid SLE Behcet’s disease

Bacterial Listeria monocytogenes Streptococcus pneumoniae Haemophilus influenzae Neisseria meningitides Viral: Enterovirus, HIV, HSV, VZV, CMV, EBV, and others Sub-acute meningitis Cryptococcus neoformans Listeria monocytogenes Mycobacterium tuberculosis Coccidioides immitis Strongyloides stercoralis Lymphoma Focal brain lesion Toxoplasma gondii Aspergillus spp. Nocardia spp. Cryptococcus neoformans Mycobacterium TB JC virus (PML)   • Usually caused by gram negative organisms and may be accompanied by septicemia.   •   Candida albicans→ immunosuppressed . Acute meningitis

UTI

Infectious causes

Comments   • CNS involvement occurs in many rheumatic diseases, including granulomatosis with polyangiitis, polyarteritis nodosa, Behcet’s disease, and most frequently SLE.   • Immunosuppressive therapy increases the risk of CNS infections which may be indistinguishable from CNS manifestation of underlying rheumatic disease.   • The usual signs and symptoms of life-­ threatening CNS infection may be greatly diminished or absent because of the effect of immunosuppressive therapy.   • In lupus cerebritis, clinical and LP findings are almost similar to bacterial meningitis with the exception of:    – Less nick stiffness in lupus cerebritis.    – Normal lactic acid level (↑ bacterial).    – Decreased C4 level in the CSF.

  • The incidence of UTI in immunosuppressed patients other than diabetics or renal transplant recipients is not higher than the incidence in immunocompetent individuals.   • Neutropenia blunts the clinical manifestations of UTI and predisposes to bacteremia.

11  Fever and Rheumatology

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Table 11.5 (continued) Disease Skin infection

Septic arthritis

Osteomyelitis

Causes   • Staphylococcus aureus, group A streptococci, and GNR. Neutropenic Initial infection: Gram negative and gram positive Subsequent infection: Antibiotic-resistant bacteria, fungi Cellular immune Bacterial Nocardia spp., deficiency atypical mycobacteria Viral VZV, HSV, CMV Fungal Cryptococcus species Histoplasma species   • Staphylococcus aureus (most common), other species Streptococcus pneumoniae, groups B, C, and G Strep, Haemophilus, and gram-negative bacilli.   • Consider →OI such as atypical mycobacteria and Pneumocystis jirovecii immunocompromised host.

Comments

  • The risk of septic arthritis in RA patient, irrespective of therapy, is increased by 4–15-fold.   • Diagnosis of septic arthritis in the rheumatoid patient is often delayed.   • Use of anti-TNF therapy in RA is associated with a doubling in the risk of septic arthritis.   • DMARDS can predispose some patients with rheumatoid arthritis to septic arthritis.

Usually monomicrobial → S. aureus (most common), Mycobacteria Contiguous Polymicrobial or monomicrobial → Staphylococcus aureus, coagulasenegative staphylococci, and (aerobic gram + anaerobic GPC and GNR) In immunocompromised patients consider →Aspergillus spp., Candida albicans, Mycobacteria spp., Salmonella spp., or Streptococcus pneumonia

Haematogenous

(continued)

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Table 11.5 (continued) Disease Bacteremia or fungemia

Causes   • The presentation and etiology of bacteremia or fungemia is similar to that in other patients.   • Disseminated Neisseria and non-typhoid Salmonella infections are more common in SLE patients.

Viral infection

  • Viruses can cause both systemic and organ-specific disease.   • The most common viral infections in patients with SLE are parvovirus B19 and CMV. Other herpesviruses are common in immunosuppressed SLE patients.   • Viral infection can be easily confused with a lupus flare due to significant overlap in the features induced by acute viral infections (fever, arthralgia, malaise, cutaneous rash, lymphadenopathy, and cytopenia) and those observed in active SLE.   • Acute viral infections are not adequately investigated in SLE patients and are only suspected after rolling out other causes of fever.   • The differential diagnosis of SLE patients presenting with fever suspected to be of infectious origin should consider not only common bacterial infections but also opportunistic viral infections, especially in patients with severe SLE involvement or those who are on immunosuppressive therapy. This group of patient should have a detailed physical examination, serologic studies, and invasive organ-specific diagnostic procedures to rule out an underlying viral infection.

Comments Salmonella:   • Can cause serious infections in SLE patients.   • Most cases occur during periods of active SLE and may be the presenting illness of SLE.   • Although fever at presentation is the rule but 15% to 20% of patients may be afebrile. And most patients are not toxic or septic on admission.   • Clinical syndromes include gastroenteritis, arthritis, and pneumonia. Less commonly diagnoses included cellulitis, osteomyelitis, urinary tract infection, or meningitis. Neisseria:   • Patients are often young sexually active women with renal disease and low C3 and C4 levels.   • Arthritis is a common presentation of disseminated Neisseria infection and less commonly meningitis and endocarditis.

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Table 11.6  Rheumatic manifestations of hepatitis B virus

Rheumatic manifestation

Systemic involvement

Serum HBs antigen Serum free antibody to HBs antigen

Acute hepatitis B Transient symmetrical polyarthritis Evanescent erythematous urticarial or petechial rash Present during rheumatic prodrome Present in convalescent phase

Chronic active hepatitis B Transient asymmetrical arthritis or arthralgia Erythematous rash rarely reported

Polyarteritis nodosa Symmetrical polyarthritis in 50%

Mixed cryoglobulinemia Chronic polyarthralgia, rarely arthritis (skin: Purpura, ulceration), kidney, liver and neuropathy

Variable

Peripheral neuropathy, CNS, muscle, liver, skin, intestines, kidneys, and heart Up to 40%

Rarely present

Not present

Rarely present

Present in 48%

abnormality usually manifest as arthralgias which have a fleeting nature which have a fleeting nature (Table 11.6).

resulting from the body’s immune system interaction with the infectious agent antigens with the subsequent immune complex formation that will be deposited in various parts of the body elicit11.5.1.4 Polyarteritis Nodosa ing an inflammatory reaction that damage the • The incidence of HBs antigenemia in polyar- involved organs. Patients who are infected with teritis nodosa is varied based on the criteria used HCV often have no symptoms. Anyone newly for diagnosis and the sensitivity of the technique diagnosed with arthritis or cryoglobulinemia used for detection of the HBs antigen. should be tested for HCV infection. Also, there • Clinically, these patients might present with are certain drugs used in the treatment of HCV multisystem involvement of the skin, muscles, infection, e.g., interferon can worsen a related nervous system, lungs, and polyarthritis as rheumatologic disease. well as liver disease. Arthritis is noted in 2 to 20% of HCV patients [107, 108]. The arthritis takes the form of eva11.5.1.5 Essential Mixed nescent rheumatoid-like picture in two-thirds of Cryoglobulinemia the cases and an oligoarthritis pattern in the rest. It has the following clinical features: non-­ Rheumatologic manifestations include painful thrombocytopenic purpura upon exposure to joints and muscle and fatigue, “the first and most cold, diffuse arthralgia, and generalized weak- common complain,” and less commonly patients ness and hepatosplenomegaly; rarely it is associ- might have joint swelling and vasculitis. ated with neuropathy and gangrene. Cryoglobulinemia happens when cryoglobulins (which are abnormal immunoglobulin) precipitate in cold temperature. It may affect 11.5.2 Hepatitis C Virus Arthritis the blood vessels specially during cold weather leading to “‘Raynaud’s phenomenon.” [105, Hepatitis C virus (HCV) is associated with many 106] The diagnosis of HCV can be made by findrheumatologic manifestations including those ing HCV Immunoglobulins or by detecting the related to joints, muscles, and connective tissue virus RNA.

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Table 11.7  Rheumatic manifestations of Parvovirus B19 infection Rheumatologic manifestations

Parvovirus B19 arthropathy Male 30% Children [113]   • Occur in about 8%.   • Pattern: Asymmetrical or pauciarticular   • Joint involved.It affects the knee most often   • At times children may meet criteria of juvenile idiopathic arthritis.

11.5.3 Parvovirus B19 Arthropathy Parvovirus B19 is the cause of fifth disease “slapped cheeks” or erythema infectiosum. The disease manifests by rash, arthritis/arthralgia, laboratory abnormalities, and other connective tissue diseases like syndrome. It may mimic systemic lupus (SLE) both in children and adults (Table 11.7) [109, 110]. Arthritis/arthralgia may accompany or follow the skin eruption. The rheumatologic symptoms may persist for weeks to rarely months with resolution, but recurrences are reported [111, 112]. The diagnosis of acute parvovirus infection is made by finding IgM antibody, while IgG antibody is evidence of preexisting exposure. Acute phase reactant, i.e., erythrocyte sedimentation rate and C-reactive protein are occasionally elevated. The leukocyte remains normal, but in some cases, rheumatoid factor and antinuclear antibody may be present in the acute period.

Female 59% Adults [112]   • Occur in about 60%.   • Many adult have arthritis alone without other symptoms.   • Typical pattern. Acute onset symmetrical polyarticular arthritis   • Joints involved. Proximal interphalangeal with metacarpophalangeal most commonly

percentage of patients may have potentially lethal forms known as hemorrhagic fever and dengue shock syndrome [115].

11.5.5 Septic Arthritis

It is a bacterial infection of the joint that is usually curable with treatment, but morbidity and mortality are still significant specially in patients who have underlying rheumatoid arthritis, patients who have prosthetic joints, elderly patients, and patients who have severe and multiple comorbidities. Incidence of septic arthritis 10 cases per 100,000 patient-years in general population in Europe [116]. Incidence of septic arthritis in patients with rheumatoid arthritis. (Based on prospective British Society for Rheumatology Biologics Register) 1.8 cases per 1,000 patient-years in 3,673 patients taking non-biologic disease-modifying antirheumatic drugs, where 4.2 cases per 1,000 patient-years in 11,881 patients taking anti-tumor 11.5.4 Dengue Virus necrosis factor therapy. Usually it is monoarthritis, but up to 20% of • The classical features of dengue virus (DV) patients have infection in >1 joint “polyarticular.” are acute febrile illness, headache, and muscle [116] The joints mostly affected are knee (which and joint pain. It is also referred to as “break-­ is the most common affected joint approximately bone fever.” [114] Arthralgia occurs in 60 to 50%) followed by the hip, shoulder, and then elbow 80% of the patients infected with DV. [120]. In IV drug users, axial skeletal joints are mainly involved often with Staphylococcus aureus. Investigations may reveal leucopenia, thromThe most common causes of septic arthritis in bocytopenia, and elevated liver enzymes. A small adults are: [116]

11  Fever and Rheumatology

• Staphylococcus aureus most frequent causative agent, followed by Streptococcus. • Neisseria gonorrhoeae, but it is considered separately as disseminated gonococcal infection. • Gram negatives, Haemophilus, are usually seen in older patients. In IV drug users, septic arthritis is frequently duo to methicillin-resistant Staphylococcus (MRSA), mixed infections, fungal infections, or unusual organisms [116]. Patients may have 1–2  weeks history of joint pain, tenderness, warmth, redness, restricted motion, loss of function, and fever. Joint-related risk factors for infection are joint prosthesis, intra-articular injection, and joint trauma [119]. Fever occurs in about one-third of patients [116]. “Large joints in legs (hips and knees) are the typical sites of infection.” [116–118] Septic arthritis is diagnosed by clinical signs (hot, red, tender, swollen, restricted) with any of the following: • Pathogenic organism in synovial fluid detected by culture and gram stain. • Pathogenic organism isolated in blood or other site. • Turbid synovial fluid in patient with recent antibiotic treatment. • Synovial WBC count more than 30,000. • Leukocytosis.

11.5.6 Poncet’s Disease (Reactive Arthritis Associated with Tuberculosis) [121] There is a new pattern of reactive arthritis associated with tuberculosis (TB), identified as Poncet’s disease (PD) or tuberculous rheumatism, which is a sterile reactive arthritis that can emerge during any stage of acute TB infection. In a retrospective case series study, seven cases of Poncet’s disease were identified:

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• The most common presentation was extrapulmonary with involvement. –– of multiple sites. • Six out of seven patients developed arthritis after initiation of anti-TB drugs. • One patient developed polyarthritis after completion of anti-TB medication. • Asymmetrical polyarthritis was the most common pattern of joints involvement. The resolution of the arthritis was with symptomatic treatment and continuation of anti-TB drugs. PD may manifest in a variable pattern during the course of active tuberculous infection. Physicians should be aware of this rare complication associated with a common disease to prevent delay in diagnosis and initiation of appropriate treatment.

11.6 V  accination in Adult Patient with Autoimmune Inflammatory Rheumatic Diseases (AIIRD) 11.6.1 Introduction It is well known that vaccination is one of the most effective measures to prevent infections and as discussed earlier in this chapter patient with autoimmune inflammatory rheumatic diseases is at increased risk of infection compared to the normal population with the respiratory tract being the most affected organ [122, 123]. However, vaccination of immunocompromised patients is challenging both regarding efficacy and safety. The efficacy of vaccinations in patients with AIIRD may be reduced, and there is a potential risk of flares of the underlying AIIRD following vaccination. The two major issues to consider in vaccine administration of this group of patients are what is the expected immune response following vaccination and what are the potential for worsening the underlying disease.

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Table 11.8  Vaccinations by type Inactivated vaccines Tetanus Haemophilus influenzae type b Hepatitis A and B Human papillomavirus (HPV) Japanese encephalitis Pneumococcal Meningococcal Typhoid (IM) Inactivated polio Inactivated influenza

Live vaccines Adenovirus Herpes zoster (shingles) Measles, mumps, rubella Varicella Rotavirus Yellow fever BCG Typhoid (oral) Live polio (oral) Live influenza (nasal spray)

11.6.2 General Rules All inactivated vaccines can be administered safely to persons with AIIRD whether the vaccine is a killed whole organism or a recombinant, subunit, toxoid, polysaccharide, or polysaccharide protein-conjugate vaccine. Live viral and bacterial vaccines should be avoided whenever possible in immunosuppressed patients with AIIRD because it might lead to severe infection in immunocompromised patients (Table  11.8). Table 11.9 shows vaccinations recommendations in adult patient with autoimmune inflammatory rheumatic diseases (AIIRD).

Diphtheria Rabies Cholera

Table 11.9  Vaccination recommendation in AIIRD * [124–127] Inactivated influenza vaccine Pneumococcal polysaccharide (PPV23) Pneumococcal 13 valent conjugate (PCV13) Tetanus toxoid vaccine Human papilloma virus vaccine (HPV) Hepatitis A vaccine Hepatitis B vaccine

Give annually  • Age 19 to 64 y. (one dose + revaccination dose)  • All adults ≥65 y of age.  • Age 19 to 64 y.  • No revaccination.

Special consideration Minimum interval of 5 y between PPSV23 doses should be maintained

Like general population

In case of major and/or contaminated wounds in patients who received rituximab within the last 24 W ⇨ tetanus immunoglobulin’s should be administered

Like general population Only recommended in patient at increased risk EULAR/ACIP ⇨ only for patient at increased risk ACR:  • Should be given before starting DMARD or biologic drug.  • If not ⇨ give to patients already on DMARD or biologic drug.

Protective antibodies against hepatitis A should be absent Protective antibodies against hepatitis B should be absent

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Table 11.9 (continued) Inactivated influenza vaccine Herpes zoster vaccine (HZV)

Asplenic/hyposplenic

Travelers with AIIRD

PCP prophylaxis

Give annually Special circumstances

Give:  • Influenza vaccine.  • Pneumococcal vaccine.  • Meningococcal C vaccine.  • Haemophilus influenzae B. Vaccinations according to the general rules with some exception

Special circumstance

Special consideration  • Before starting DMARDS or biologic agent.  • At least 14 days before initiation of immunosuppressive therapy or 3 months after immunosuppression has stopped.  • The following conditions not consider sufficiently immunosuppressive to be a contraindication for HZV:    – MTX ( 100/min.

1 point 4 1 point 1 point -2 point

5

Immobilization >3 days or surgery in previous 4 weeks Previous PE or DVT

6 7

Hemoptysis Malignancy

3 points 3 points 1.5 points 1.5 points 1.5 points 1 points 1 points

If Patient has symptoms or signs of deep venous thrombosis e.g. (swelling, redness, cramps, calf or leg pain, leg edema, warmth, tenderness, superficial dilation of veins). 3 points for each Other diagnosis less likely than pulmonary embolism

Tachycardia HR>100 bpm MODIFIED WELLS Criteria for PE Probability

Patients who are Immobile more than 3 days or did surgery in last 4 weeks

1.5 point for each

If patient had past medical history of pulmonary embolism and deep venous throm bosis

History of hemoptysis

History of cancer

Fig. 12.4  Modified Wells Criteria for PE Probability

1 point for each

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Fig. 12.5  Probability of DVT algorithm

Probability of DVT

Low

High and moderate

USD

Negative ultrasound

Follow up and repeat DUS

D-dimer

Positive ultrasound

Negative ultrasound

DVT confirmed

Rule out DVT

D-dimer (ELISA)

Low or intermediate Clinical probability of PE

Positive ultrasound

DUS

Negative → exclude PE

Positive

High

CT pulmonary angiography

Contraindication to CT

ventilation/ perfusion V/Q

Fig. 12.6  Clinical probability of PE

nary angiography (the gold standard) [39] is required. If patient’s risk for PE is high, CT pulmonary angiography should be done, but in situation where contraindication for contrast is used in CT angiogram such as in patients with renal failure, ventilation/perfusion (V/Q) scan can be done [43, 51, 53] (Fig. 12.6). Pulmonary embolism rule out criteria (PERC) is used in patients who are less likely to have PE (4 points or less); factors of PERC are age 4

281

Probability of PE

Less likely if ≤ 4

Pulmonary Embolism role out criteria (PERC)

CT Pulmonary Angiogram PERC

If score > 6, add anticoagulation

1- Age < 50 years 2- Heart rate 945

Negative

4- No Hemoptysis 5- No unilateral leg swelling

Positive if not met PERC

Negative D dimer

6- No trauma or surgery within past 4 weeks 7- No prior DVT or PE 8- No use of estrogen or progesterone hormones

No further evaluation need R/O PE

Fig. 12.7  Probability of Pulmonary Embolism algorithm

V1–V4, right bundle branch block, S1Q3T3, and QR in V1 or P pulmonale [39, 43, 44]. Arterial blood gases can show hypoxemia, hypocapnia, and widened (A-a) O2 gradient [44]. In patients with PE, check troponin and brain natriuretic peptide (BNP) levels, since their high levels are associated with RV strain and linked to increased mortality in PE [44]. Laboratory investigations include general and specific workup. Generally, for all patients with thrombosis, full blood count, renal and liver function, and coagulation profile need to be done. Specific workup for thrombophilia and hereditary hypercoagulable disorders, this includes: Factor V Leiden, Prothrombin 20210A, Protein C and S, Antithrombin III [38], as they also can present in autoimmune rheumatic disorders such as SLE.  Acquired hypercoagulable states includes anti- aPL antibodies (LA, ACA, β2GP1) should be done in idiopathic thrombosis or if there multiple thrombi, HLA-B51 test for BD if thrombosis is at an usual site (Bud Chairi syndrome) or both arterial and venous thrombi or idiopathic CVT should be considered [55].

Other blood workup includes acute phase reactants that measure disease activity (CRP, ESR), since their high levels correlate with high risk of thrombosis and atherosclerosis in certain diseases such as RA [19].

12.4 Management of Thrombosis in Rheumatic Diseases, Prophylaxis, and Secondary Prevention of Thrombosis 12.4.1 Management of Thrombosis in Rheumatic Diseases There are no specific recommendations for the management of thrombosis in patients with rheumatic disorders, the same plan of treatment as of patients with other diseases and general population. Anticoagulation with intravenous unfractionated heparin (UFH) or subcutaneous low molecular weight heparin (LMWH), followed by warfarin, is the initial treatment strategy for cases with acute thrombosis [57].

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Treatment of patients with PE depends on clinical probability of pulmonary embolism and hemodynamic stability of patients, initial treatment with anticoagulant if clinical probability is high or intermediate and cannot get the investigation within 4 h and in case of low probability and investigation deferred for 24 hours, anticoagulant therapy include LMWH, or fondaparinux, both are administered subcutaneously, do not require monitoring of PT and APTT, and not to be used in renal failure, UFH is administered intravenously and it is preferred in massive PE. If there is contraindication to anticoagulant, then inferior vena cava filter should be considered. Thrombolytic therapy is used in patients who have hemodynamic instability [40, 41] (Fig. 12.8). In patients with DVT, LMWH is recommended, as it is superior to UFH especially in pregnant and patient with cancer, but it should not be used in patient with renal failure; they should be treated with unfractionated heparin (Fig.  12.9); warfarin should be started together with LMWH until targeted INR is reached; inferior vena cava filter is indicated in patient with

contraindication to anticoagulation therapy [45, 48, 56] (Fig. 12.10). Compression stocking is used within 1 month of DVT diagnosis to prevent post-thrombotic syndrome and for at least 1 year after diagnosis [45, 56]. Anticoagulation with warfarin had been associated with several disadvantages related to the drug itself such as slow onset of action, variable pharmacologic effects, food-drug interactions, prolonged half-life, and the need for close monitoring of INR [65]. However, several large studies have been done in this field, and researchers had found that the NOACs are now emerging as the alternative anticoagulation therapy to conventional therapy for patients with acute VTE; the advantages of these novel anticoagulant therapy are many and overcome the troubles of warfarin therapy, such as the fixed therapeutic dose, without the need of dose adjustment; they do not require routine laboratory monitoring of PT and INR.  They reach their peak efficacy within 1 to 4 h after ingestion; thus a prolonged period of bridging therapy is not required when switching from initial treatment with UFH or LMWH to

Treatment of Pulmonary embolism

Thrombolytic therapy

Step one 1-Anticoagulantion with subcutaneous (SC) LMWH, fondaparinux, or UFH (IV or SC) if CPTP:

moderate and investigation deferred for 4 hrs

High

low and investigation deferred for 24 hrs

Inferior vena cava filter

Contraindication to anticoagulantion (recent surgery, hemorrhagic stroke, active bleeding)

Hemodynamic instability

{1 PLUS 2} Confirmed PE diagnosis

1- Anticoagulation as in step 1for at least 5 days, until targeted INR, continue overlap for 24-48 hrs, then discontinue 2- Oral warfarin (monitor INR) 3- If new oral anticoagulants are considered, can be given without step 1, (INR monitoring is not required)

Fig. 12.8  Treatment of PE

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Fig. 12.9 Characteristics of special population and types of heparin

Special Population

Renal impairment

UFH

cancer

pregnancy

LMWH

Obesity>100 kg

Laboratory monitoring of LMWH

Treatment of Acute DVT

Contraindication to anticoagulantion (recent surgery, hemorrhagic stroke, active bleeding)

NO

Anticoagulation

subcutaneous LMWH, fondaparinux, or UFH (SC or IV) (for at least five days until targeted INR, continue overlap for 24-48 hrs, then discontinue

Warfarin (monitor INR)

Fig. 12.10  Management of DVT algorithm.

YES

Inferior vena cava filter

OR, New oral anticoagulants (NOAC) 1- Rivaroxaban 2- Apixaban (factor Xa inhibitors) 3- Dabigatran (direct thrombin inhibitor) (No monitoring required with NOAC)

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these novel agents and less risks of major bleeding. Unfortunately, the antidote for bleeding events is not available yet [64,65,66]. No data is available regarding the safety of NOACs in pregnancy, for which it should be avoided in a pregnant patient and also in some other conditions such as patients with mechanical heart valves and in severe renal insufficiency [65]. Two groups of NOACs are available, factor Xa inhibitors (rivaroxaban, apixaban) and direct thrombin inhibitors (dabigatran). The safety and efficacy of these agents for the treatment and prevention of recurrent VTE have been studied by large randomized prospective trials [64]. Apixaban has a rapid onset of action and is approved for use in the prevention of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation (AF) and in the primary prevention of VTE in adult patients who have undergone elective total hip or total knee arthroplasty [65]. Apixaban is effective for the prevention of recurrent VTE if patients complete 6 to 12 months of anticoagulant therapy for acute VTE, with major bleeding risk similar to those for placebo. Therapy with apixaban was compared with conventional anticoagulant therapy in patients with acute symptomatic VTE in the AMPLIFY trial (Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy) [66]. The AMPLIFY study has very impressive results and concluded that a fixed-dose oral apixaban alone was as effective as conventional treatment which consists of enoxaparin followed by warfarin and was associated with a clinically relevant reduction of 69% in major bleeding, and its efficacy in patients with PE was similar to that in the patients with DVT. Moreover, the efficacy and the reduction in major bleeding with apixaban were consistent with that of warfarin, but clinically relevant n­ on-­major bleeding were less. Interestingly, The efficacy and safety of apixaban were consistent in all patients participated in the trial including patients older than 75  years, obese patients of more than 100  kg, use of parenteral anticoagulant treatment before randomization, and treatment dura-

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tion. AMPLIFY trial results are very promising and encouraging to consider apixaban a safe and effective regimen for the initial and long-term VTE treatment [66].

12.4.1.1 Special Consideration for Thrombosis in Rheumatic Disorders • Patients with rheumatic diseases and thrombosis need a long-term management (indefinite) for thrombosis especially those with aPL autoantibodies to prevent recurrent thrombosis, that is, secondary thrombosis prevention; they require the optimal intensity of anticoagulation with warfarin [30, 57]. • Several studies had proven that high-intensity treatment with warfarin to maintain INR = 3.0 with or without low-dose aspirin was more effective than moderate-intensity warfarin or low-dose aspirin for the prevention of recurrent thrombosis in aPL-positive patients, but, recently, some trials demonstrated that high-­ intensity anticoagulation (INR 3.1–4.0) was no better than moderate intensity (INR 2.0– 3.0). So, moderate-intensity anticoagulation is the current standard of treatment of first venous thrombosis [57–60] (Fig. 12.9). • For the management of acute DVT in BD immunosuppressive agents such as corticosteroids, azathioprine, cyclophosphamide, and cyclosporine A are recommended, but there is no evidence of benefit from, and uncontrolled experience with anticoagulation, use of antiplatelet or antifibrinolytic agents in the management of DVT or for the use of anticoagulation in arterial thrombosis in patients with BD, in patients with CVT (dural sinus thrombosis) treatment with is corticosteroids is recommended (modified EULAR 2008 recommendation) [59]. Anticoagulant therapy must be used cautiously and only after systemic immunosuppressant, and if thrombi are not extensive, antiplatelet treatment with lowdose aspirin is probably sufficient [61]. • • In patients with a low-risk aPL profile, who had first venous thrombosis in the presence of a known transient risk factor, anticoagulation could be limited to 3–6 months [30].

12  Thrombosis in Rheumatological Diseases

12.4.2 Prophylaxis and Secondary Thrombosis Prevention in Rheumatic Disorders • Daily ASA in doses of 75–325 mg are suitable for inhibition of platelet aggregation for prophylaxis against cardiovascular events in RA patients [19]. • Prophylaxis use of LMWH to prevent venous thrombosis during periods of immobilization, as immobilization in RA patients is related to disease activity and inflammation [19]. • ASA (75–150  mg/day) is recommended for the prevention of cerebrovascular events and vision loss in GCA, and it should be also considered for the primary prevention of cardiovascular events in TAK [5].

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12.4.2.3 P  rimary Prophylaxis in High-­ Risk Situations All patients with aPL positivity should receive usual doses of LMWH in high-risk situations, such as surgery, prolonged immobilization, and puerperium [30]; the same is applied for all patients with other rheumatic disorders.

12.4.2.4 Secondary Prophylaxis in Patients with Positive aPL Antibodies • Patient who suffered from either arterial or venous thrombosis and aPL who do not fulfill criteria for APS should be managed in the same manner as aPL-negative patients with similar thrombotic events [30]. • Recurrent venous thrombosis has been reported in patients with APS at 3% to 24%. Secondary 12.4.2.1 Primary Prophylaxis in SLE prophylaxis with high-intensity warfarin Patients (INR  =  3–4), or moderate-intensity warfarin • HCQ reduces thrombotic risk and disease-­ (INR = 2–3) plus ASA is recommended [60]. related morbidity and mortality in SLE and is • Treatment of APS patients with arterial recommended for all patients unless it is conthrombosis is controversial, and only ASA traindicated [10]. 325 mg/day can be given or moderate-inten• HCQ plus low-dose ASA is recommended for sity warfarin (INR = 2–3) alone or combined SLE patients with positive LA or ACA low-dose ASA or high-intensity warfarin (medium-high titers) [30]. (INR > 3) [30, 60]. • In pregnant women, with recurrent fetal loss, a 12.4.2.2 Primary Prophylaxis in APS combination of ASA and heparin is recomPatients mended. ASA 81  mg/day should be started • In asymptomatic individuals, aPL antibodies when attempting conception, and when the positivity is an incidental finding; thus, pripregnancy is confirmed, heparin subcutanemary prophylaxis can be considered with ASA ously should be started as LMW (enoxaparin 81 mg per day [59, 60]. 1  mg/kg/day, dalteparin 5000  units/day, or • Healthy individuals, with positive aPL antinadroparin 3800  units/day) or as unfractionbodies in high titers and with no thrombotic ated (5000–10,000 units 12 hourly) [60]. manifestations, should be advised for a pri- • In catastrophic APS, a combination therapy is mary prophylaxis with ASA 325  mg orally required with (1) anticoagulation with intravedaily [60]. nous (IV) heparin for 7–10 days, (2) steroids • HCQ 400 mg orally daily decreases aPL antiin high doses with (IV) methylprednisolone body titers and thus protects from further 1 g daily for 3 or more days, (3) IV immune thrombotic episode; that is based on trials in globulin (IVIG) 0.4  mg/kg/body weight/day animal models and an indirect evidence from for 4–5  days, and/or (4) plasmapheresis for human studies, so more studies are needed to 3–5  days at least with fresh frozen plasma prove this effect of HCQ for standard recomreplacement [60]. mendation in healthy aPL-positive patients (See Fig. 12.11 for treatment and second[60] (Fig. 12.11). ary prophylaxis of thrombosis in APS)

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Treatment recommendations in APS, for persistently positive aPL antibodies with heparin, warfarin and ASA

Asymptomatic

Thrombocytopenia

Catastrophic APS

Thrombosis

Venous

No treatment consider ASA 81 mg/day in high risk patients with multiple non-aPL cardiovascular risk factors

Arterial

Recurrent

Warfarin, highintensity dose (INR 34) +/-low dose ASA

Warfarin, mediumintensity dose (INR 2.5) indefinitely

>50,000 /mm3

No treatment

40 years, tobacco use, previous radiation exposure, certain occupational exposures (dyes, benzenes, aromatic amines) and medications such as cyclophosphamide Transient causes: recent exercis, sexual activity and menstruation The upper urinary tract causes (glomerular or non-glomerular): smoking history, fever, weight loss, flank pain, trauma history, history of chronic diseases or cancers such as DM, HTN, SLE, TB, HIV, Sickle cell anemia, or Lymphoma The lower urinary tract causes: Usually present with dysuria, suprapubic pain, frequency and urgency. UTI: fever, dysuria and suprapubic pain

Fig. 14.2  approach to a patient with hematuria.

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Macroscopic

Microscopic

Painless Painful

1-Kidney stones

Isolated hematuria

2-Pyelonephri tis 3-Trauma 4-Cystic rupture in PCKD 5-Renal infarction

Cellular casts, dysmorphic RBCs, proteinuria or renal dysfunction

Suspect malignancy

Cellular casts, dysmorphic RBCs, proteinuria or renal dysfunction

Suspect GN Suspect GN

Pyuria

Isolated hematuria (no proteinuria)

Suspect UTI

Check urine culture

Elderly or with risk factors for malignancy

Young age

Periodic follow up

CT scan cystoscopy Nephrology referral

Nephrology referral

CT scan

Need to rule out malignancy

CT Scan Cystoscopy

Fig. 14.3  Classification of hematuria

14.5 Renal Involvement in Different Rheumatic Diseases Rheumatic diseases are frequently associated with renal complications. These complications include vascular, glomerular, and tubulointerstitial changes. Drug-induced renal impairment should be included in the differential diagnosis of renal complications in a rheumatic patient. Renal involvement clinically manifests in many different ways. The spectrum ranges from slight functional disorders such as slight erythrocyturia/proteinuria with normal renal function

to rapidly progressive renal failure. Table  14.3 provides a summary of renal involvement in different rheumatic diseases.

14.6 Lupus Nephritis (LN) Renal involvement is common in SLE.  It is the leading cause of morbidity and mortality in patients with lupus, characterized by the loss of self-tolerance, production of autoantibody, and development of immune complexes that deposit in the kidney to induce nephritis. Proteinuria is one of the most commonly observed abnormalities in patients with lupus nephritis [6].

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Figure  14.4 provides an overview of pathogenesis, clinical manifestations, and complications of lupus nephritis.

14.6.1 Diagnostic Criteria Criteria for lupus nephritis in patients with SLE include any of the following conditions (Table 14.1): 1. Persistent proteinuria. • 500 mg/24 h protein • 3+ protein on urine dipstick • Spot urine protein/creatinine ratio  >  0.5 mg/mg. 2. Cellular casts. 3. Active urinary sediment (> 5 red blood cells/ high power field [RBC/hpf], > 5 white blood cells[WBC]/hpf in the absence of infection, or cellular casts limited to RBC or WBC casts). 4. Renal biopsy: Immune complex-mediated glomerulonephritis compatible with lupus nephritis. 5. Opinion of rheumatologist or nephrologist [11].

14.6.2 Treatment The American College of Rheumatology (ACR) recommends treatment according to the International Society of Nephrology/Renal Pathology Society (ISN/ RPS) classification of lupus nephritis. (Check sect. 3 for full presentation of the recommendation for management guidelines). Response to treatment is based on several factors including age, gender, location, and race/ethnicity (Table 14.2) [14].

14.6.3 Adjunctive Treatments 1. Hydroxychloroquine for all patients with SLE unless contraindicated.

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2. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers if proteinuria ≥500 mg/24 h [15] 3. Statin therapy if LDL cholesterol >100 mg/dL (2.6 mmol/L). 4. Control hypertension at a target of ≤130/80 mm Hg [11] Note: Patients with lupus should remain on antimalarial therapy even during disease quiescence as it was shown to be associated with ­associated with reduced risk of renal damage, improved survival, and decreased incidence of lupus flares [16].

14.7 Sjögren’s Syndrome Sjögren’s syndrome is a chronic inflammatory disorder characterized by lymphocytic infiltration of the lacrimal and salivary glands which result in dryness of the eyes and mouth [17]. Systemic features may include arthritis, renal, hematopoietic, pulmonary involvement, and vasculitis (Fig.  14.5). These manifestations are secondary to vasculitis, autoantibody-mediated mechanisms, or lymphocytic infiltration of the target organs. The prevalence of renal involvement ranges from 2 to 67% [22].

14.8 Cryoglobulinemic Syndrome (CG) Cryoglobulinemic vasculitis is an immune-­ complex-mediated disease caused by the deposition of cryoglobulins in the small- and medium-sized arteries and veins. Renal involvement is noted in around 20% of patients with mixed cryoglobulinemic vasculitis and usually diagnosed 2.5  years after the disease onset. Membranoproliferative glomerulonephritis is reported in around 80% of patients [23]. Figure 14.6 provides an overview of renal involvements in CG.

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Increase in mesangial cells and mesangial matrix, inflammation, cellular proliferation, basement membrane abnormalities and immune complex deposition (immunoglobulin M, immunoglobulin G, immunoglobulin A, complement components)

Pathogenesis

:

Histologic classification based on signs of activity and chronicity activity index: proliferative change, necrosis/karyorrhexis, cellular crescents, leukocyte infiltration, hyaline thrombi, interstitial inflammation chronicity index: sclerotic glomeruli, fibrous crescents, tubular atrophy, interstitial fibrosis

Chief complaint: Usually asymptomatic History of presenting illness:

History Lupus Nephritis

1- Foamy urine or nocturia (early signs of glomerular or tubular dysfunction) 2- Microscopic hematuria, macroscopic hematuria (rare)

Physical examnation

Factors associated with worse outcome

Complications:

- SLE findings - Periphral edema (nephrotic syndrome)

Elevated serum creatinine, total cholesterol levels and proteinuria

1- Chronic kidney disease, nephritic syndrome, rapidly progressive renal failure (ISN/RPS Class IV) 2- Severe extra-renal manifestations such as lupus cerebritis, lupus pneumonitis

Fig. 14.4  Overview of pathogenesis, clinical manifestations, and complications of lupus nephritis [7–9]

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Table 14.1  Recommended workup for suspected lupus nephritis Tests

Findings Serum creatinine Antinuclear antibodies (ANA)

Anti-double-strand DNA antibodies (anti ds-DNA) Antiphospholipid antibodies (APLA) Anti-C1q antibodies Complement 3 (C3) and complement 4 (C4)

Urine studies

Persistent proteinuria

Dysmorphic erythrocytes RBC or WBC cells

Cellular casts Lipiduria Renal biopsy

Indications  1 to confirm suspected nephritis  2 to evaluate disease activity and damage  3 to determine appropriate therapy  4 to make sure that the type, duration, and intensity of treatment matches the severity of disease  5 to predict outcome and identify the alternative causes of renal disease

Analysis To evaluate renal functions [6] Frequently positive in patient with connective tissue disease and high sensitive for SLE and drug-induced lupus [6] High in patient with LN, it plays an important role in induction of tissue damage, and it correlates with disease activity [6] To evaluate autoimmune disease especially SLE, its presence means increase risk of thrombosis [6] It is sensitive and specific to diagnosis of lupus nephritis and evaluating the disease activity [10] Lack of C3 and C4 may indicate lupus nephritis because the presences of these complement components exert a protective effect against disease onset, although it may be normal [6] - Increases incrementally within severity classes - >500 mg/24 h protein - >3+ protein on urine dipstick - Spot urine protein/creatinine ratio > 0.5 [6, 11] - Indicate inflammatory glomerular disease [6, 11] - (> 5 red blood cells/high power field [RBC/hpf], > 5 white blood cells[WBC]/hpf in the absence of infection - Indicate glomerulonephritis or tubulointerstitial disease [6, 11] - RBC or WBC casts which indicate inflammatory glomerular disease [6, 11] - May result from abnormal glomerular permeability [6, 11] American College of Rheumatology (ACR) recommendations - Biopsy is highly recommended in patients with systemic lupus erythematosus with the following:    Increasing serum creatinine without alternative cause (such as sepsis, hypovolemia, or medication induced).    Confirmed proteinuria ≥1000 mg/24 h (either 24-hr urine specimens or spot protein/creatinine ratios).    Combinations of following (confirmed in ≥2 tests done within short period and in the absence of alternative causes).    Proteinuria ≥500 mg/24 h plus hematuria (≥ 5 red blood cells per high power field).    Proteinuria ≥500 mg/24 h plus cellular casts.    All patients with clinical evidence of active lupus nephritis, previously untreated, should have renal biopsy to classify glomerular disease by current International Society of Nephrology/Renal Pathology Society (ISN/ RPS) classification (unless biopsy is strongly contraindicated) [11] Second biopsy: To detect disease progression Indications:  1. When the patient does not respond to therapy  2. In case of worsening of renal function [12]

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Table 14.2  Summary of the classification and treatment of lupus nephritis [11, 13] Classifications of lupus nephritis Class I (minimal mesangial LN) and class II (mesangial proliferative LN) Class III LN (focal LN) and class IV LN (diffuse LN)

Class V LN (membranous LN)

Class VI LN (advanced sclerosis LN)

Treatment Treated as dictated by the extra-renal clinical manifestations of lupus

Initial therapy: Corticosteroids (1 mg/kg, to be tapered according to clinical response) combined with either cyclophosphamide (500 mg IV every 2 weeks for 6 doses) or mycophenolate mofetil (up to 3 g per day as tolerated) Maintenance therapy: Mycophenolate mofetil (1–2 g/d in divided doses) or azathioprine (1.5–2.5 mg/kg/d) and low-dose oral corticosteroids (≤10 mg/d prednisone equivalent) Non-nephrotic-range proteinuria: Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Corticosteroids and immunosuppressive therapy use is dictated by the presence of extrarenal manifestations of lupus Persistent nephrotic-range proteinuria: Corticosteroids plus an additional immunosuppressive agent—(Cyclophosphamide, tacrolimus, cyclosporine), mycophenolate mofetil or azathioprine Treated with corticosteroids and immunosuppressive therapy only as dictated by the extra-renal manifestations of lupus. Discussion of renal replacement therapy (dialysis vs kidney transplant)

14.9 Scleroderma Scleroderma is manifested by widespread progressive fibrosis of the skin and internal organs due to accumulation of collagen. Renal involvement occurs in around half of the patients and is manifested as mild proteinuria, worsening kidney function, and/or hypertension (Fig.  14.7) [26]. Scleroderma renal crisis is the most serious renal manifestation which occurs in 5 to 10% of patients with systemic sclerosis, more commonly in diffuse cutaneous systemic sclerosis [27].

14.9.1 Rheumatoid Arthritis (RA) Rheumatoid arthritis is a systemic inflammatory disorder of unknown etiology that primarily involves the joints. It has been reported that the annual incidence of rheumatoid arthritis is around 40 per 100,000. Females are affected two to three times more often than males, and the peak onset is between 50 and 75 years of age [28]. An observational study has shown that the incidence of impaired kidney function is higher in patients

with rheumatoid arthritis; these changes were anticipated by many factors like cardiovascular disease, dyslipidemia, elevated sedimentation rate in the first year of rheumatoid arthritis, and NSAIDs use [29]. Figure 14.8 provides an overview of renal involvement in RA.

14.9.2 Renal Involvement in Vasculitis 14.9.2.1 Polyarteritis Nodosa (PAN) It is a systemic necrotizing vasculitis of medium-­ sized and occasionally small vessels [34]. It is a rare disease and characterized by the absence of antineutrophil cytoplasmic antibodies (ANCA) [34]. Any organ can be affected including the kidneys (renal artery involvement is common and leads to stenosis, hypertension, and eventually chronic kidney disease) (Fig.  14.9). This disease spares the lungs [34]. Most cases are idiopathic; however, 33% of cases are associated with chronic HBV infection [34]. Renal disease is the most common cause of death. It is fatal if left untreated, but has favorable response to treatment [34].

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Definition

Renal complications

It is a chronic inflammatory disease characterised by lymphocytes-mediated infiltration of exocrine glands [14]

1- Tubulointerstitial nephritis 2- Glomerular diseases

Interstitial nephritis: Characterized by interstitial lymphocytic infiltrate that can damage the tubules A- Distal renal tubular acidosis (RTA): Non-anion gap metabolic acidosis and hypokalemia due to defect in distal acidification Pathogenesis Sjögren’s syndrome

B- Nephrogenic diabetes insipidus (NDI): Polyuria and hypernatremia due to resistance to the action of anti-diuretic hormone (ADH) [14,15,16]

Glomerular disease: Less common A- Membrano-proliferative glomerulonephritis B- Membranous nephropathy [14,15,16]

Treatment of renal involvment

RTA: Bicarbonate and potassium [17] NDI: Low sodium and protein diet, thiazide diuretics and NSAIDs

Glomerular disease Immunosuppressant [17]

Fig. 14.5  Renal involvement in Sjögren’s syndrome: [18–21]

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Definitions

It is a form of immune-complex mediated systemic vasculitis involving small and medium sized arteries and veins

- Types II and III CG (mixed cryoglobulinemic) are the most common forms of cryoglobulinemia, typically characterized by a triad of purpuric lesions, glomerulonephritis (nephritic), generalized weakness

Pathogenesis

- Chronic Hepatitis C virus stimulates Bcell polyclonal proliferation with subsequent polyclonal IgM production - Vessel wall damage may be the result of immune-complex mediated complement activation

Renal complications

Glomerulonephritis (often progressive type 1 membranoproliferative)

- Serologic testing for the presence of cryoglobulins

Cryoglobulinemic syndrome (CG)

- Serologic testing for hepatitis B and C Blood tests & urinalysis

- Very low levels of ‘early’ complements, especially C4 - Normal or slightly decreased levels of C3 - Blood urea nitrogen (BUN) and creatinine - Urinalysis (looking for active GN)

Renal biopsy Leukocytoclastic arteritis characterized by predominant neutrophilic infiltration with fibrinoid necrosis

Treatment of renal involvment

Fig. 14.6  Overview of renal involvements in CG [23]

Requires combined treatment with corticosteroids and cytotoxic drugs such as cyclophosphamide

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Definition

Renal complications

Pathogenesis of SRC

it is a chronic connective tissue disease. It can be subdivided into three groups: systemic sclerosis, localized scleroderma, and scleroderm-like a conditions, comprising a heterogeneous group of diseases linked by the presence of thickened, sclerotic skin

Scleroderma Renal Crisis (SRC): Occurs in 5–10% of SSc patients. It is characterized by an abrupt onset of a moderate-to-marked hypertension that is accelerated and often malignant, and acute kidney injury [19]

The pathogenesis may involve intimal thickening of the renal interlobular and arcuate arteries, which lead to decreased renal perfusion, and subsequently hyperplasia of the juxtaglomerular apparatus and increased renin release [19]

Scleroderma Risk factors of SRC: 1- Rapid and progressive skin disease 2- Corticosteroid therapy 3- Other risk factors: anaemia, HRT, pericardial effusion, cardiac insufficiency, high skin score and large joint contractures, the presence of antibodies to RNA polymerases and new cardiac events [19]

Treatment of renal involvment

Fig. 14.7  Renal involvement in scleroderma [24, 25]

Aggressive blood pressure management with ACEI is the mainstay of therapy. Other agents such as calcium channel blocking agents can be added in patients with inadequate blood pressure reduction. Blood pressure should be reduced gradually to prevent further decrease in renal perfusion and increase the risk of acute tubular necrosis [19] It can progress to ESRD and death if left untreated [20]

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Definition

Renal complications

It is a systemic inflammatory disorder of unknown etiology that primarily involves joint. Extra articular manifestation indicates the severity of the disease and is associated with increased morbidity and mortality. The kidneys are much less likely to be involved in extraarticular RA.

Membranous nephropathy Secondary amyloidosis Glomerulonephritis Rheumatoid vacuities Analgesic nephropathy

Membranous nephropathy: Occurs in patients treated with penicillamine or gold Secondary amyloidosis: Associated with chronic inflammation Glomerulonephritis: Mesangial glomerulonephritis is the most frequent histopathological finding in RA

Rheumatoid arthritis

Pathogenesis

Rheumatoid vacuities: Blood vessels inflammation may occur in patients with long standing RA. The renal findings are similar to those in other systemic vasculitis Analgesic nephropathy: Characterized by renal necrosis and chronic interstitial nephritis. It is caused by chronic analgesic use particularly phenacetin in combination with other agents

Membranous nephropathy: Treated by discontinuation of the drug Secondary amyloidosis: Treated by controling the underlying inflammatory process with medical therapy Glomerulonephritis: Treated by immunosuppressive therapy Treatment of renal involvment

Rheumatoid vacuities: Treated with regimens similar to those used in primary systemic vaseculitis Analgesic nephropathy: Treated by discontinuation of the drug

Fig. 14.8  Overview of renal involvement in RA [30–33]

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It is a systemic necrotizing vasculitis that typically affects the medium-sized arteries. Antineutophil cytoplasmic anatibodies (ANCA) are negative.

Definition

The kidneys are the most commonly involved organs. Renal involvement frequently leads to: hypertension (common) variable degrees of renal insufficiency rupture of renal arterial aneurysms can lead to perirenal hematomas Multiple renal infarctions (in severe vasculitis)

Renal complications

Polyarteritis nodosa (PAN)

Renal biopsy in classic PAN may reveal pathognomonic inflammation of the medium-sized arteries. Renal arteriography is an alternative to biopsy for the diagnosis of PNA.

Renal biopsy and urinalysis

On urinalysis: minimal proteinuria and modest hematuria (indicative of subnephrotic abnormality), but red blood cell casts (indicative of a glomerular focus of inflammation) are usually absent

Treatment of renal involvment

Treat patients with more serious disease manifestations (i.e., renal insufficiency, mesenteric artery ischemia, mononeuritis multiplex) by the combination of cyclophosphamide and glucocorticoids. Angiotensin converting enzyme (ACE) inhibitors are effective in treatment of hypertension

Fig. 14.9  Medium vessel vasculitis: polyarteritis nodosa (PAN) [34]

14.9.3 Eosinophilic Granulomatosis with Polyangiitis EGPA (Churg-Strauss) It is a systemic necrotizing vasculitis that affects small-sized muscular arteries [35]. It is a rare disease and characterized by the presence of

antineutrophil cytoplasmic antibodies (ANCA) [35]. Asthma, peripheral eosinophilia, and granulomas on histology are common associations with this disease [35]. Renal involvement can lead to pauci-immune rapidly progressive glomerulonephritis (Fig. 14.10) [35].

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Definition

It is a vasculitis of the small-sized muscular arteries and is often assocaited with vascular and extravascular granulomatosis.

Rapidly progressive or acute renal insufficiency Glomerulonephritis mainly with positive ANCA Hypertension Isolated proteinuria

Renal complications

Eosinophilic granulomatosis with polyangiitis EGPA (ChurgStrauss)

The diagnosis of EGPA is confirmed by lung biopsy or biopsy of other clinically affected tissues. Renal biopsy in classic EGPA may reveal necrotizing glomerulonephritis Renal biopsy and urinalysis On urinalysis: proteinuria, hematuria or isolated proteinuria or microscopic hematuria

Treatment of renal involvment

Treat patients with systemic glucocorticoids Cyclophosphamide is typically used in combination with glucocorticoids for patients with severe, multiorgan disease

Fig. 14.10  Eosinophilic granulomatosis with polyangiitis EGPA (Churg-Strauss) [35]

14.9.4 Granulomatosis with Polyangiitis GPA (Wegener’s) and Microscopic Polyangiitis (MPA) These are systemic vasculitides of the medium- and small-sized arteries, as well as the venules and arterioles [29]. They are known to cause many renal complications, e.g., glomerulonephritis, acute kidney injury, and proteinuria (Fig. 14.11) [29, 30]. Rapidly progressive glomerulonephritis is a common and severe feature with Wegener’s granulomatosis or proteinase-3 (PR3)-ANCA vasculitis, and it might lead to end-stage renal diseases [29, 30]. In addition, necrotizing granulomatous inflammation is the histopathologic hallmark of GPA [29, 30]. Microscopic polyangiitis or myeloperoxidase (MPO)-ANCA vasculitis are

associated with chronic renal injury more than glomerulonephritis [29, 30].

14.9.5 Henoch-Schönlein Purpura (HSP) (IgA Vasculitis) It is a systemic vasculitis of the small-sized blood vessels (the post-capillary venules), characterized by the deposition of IgA-containing immune complexes [40]. IgA vasculitis is considered the most common systemic vasculitis in children [40]. Renal involvement occurs in 20% to 100% of patients. HSP nephritis is common and generally mild in children (particularly young children) (Fig. 14.12). It is mainly presented with microscopic hematuria or proteinuria [40] (Table 14.3).

14  Renal System and Rheumatology

Definition and overview

Renal complications

Granulomatosis with polyangiitis GPA (Wegener’s) and microscopic polyangiitis (MPA)

Renal biopsy and urinalysis

323 These are systemic vasculitides of the medium and small-sized arteries, as well as the venules and arterioles. A migratory oligoarthritis is often among the initial disease manifestations of these conditions Both are associated with ANCA, have similar features on renal histology, and have similar outcomes. There are, however, several differences between these disorders The absence of ANCA does not exclude the diagnosis of GPA. The sensitivity of PR3-ANCA for GPA is related to the extent, severity, and activity of disease at the time of sampling [27]. Glomerulonephritis Acute kidney injury with hematuria and cellular casts A variable degree of proteinuria that is usually subnephrotic Rapidly progressive glomerulonephritis is common in this group of diseases [27, 28, 29].

Necrotizing granulomatous inflammation is the histopathologic hallmark of GPA Renal biopsy findings in GPA and MPA generally parallel the severity of the clinical presentation, ranging from mild focal and segmental glomerulonephritis in patients with asymptomatic hematuria and normal or near-normal renal function to a diffuse necrotizing and crescentic glomerulonephritis in patients with acute kidney injury[ 27, 28, 29].

On urine analysis: Initial manifestation: asymptomatic hematuria, with normal renal function. According to European Medicines Agency (EMA): patients with GPA Glomerulonephritis can have: hematuria associated with red cell casts, >10 dysmorphic red cells, 2+ hematuria or 2+ proteinuria on dipstick [27, 28, 29].

Treatment of renal involvment

Initial immunosuppressive therapy Cyclophosphamide or Rituximab and glucocorticoids. Maintenance therapy azathioprine or methotrexate [30].

Fig. 14.11  Granulomatosis with polyangiitis GPA (Wegener’s) and Microscopic Polyangiitis (MPA) [36–39]

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It is a systemic vasculitis of the small-sized blood vessels (most prominent in the postcapillary venules), characterized by the deposition of IgA-containing immune complexes Definition

Renal involvement ranges from 21 to 54% and is typically noted within a few days to one month after the onset of systemic symptoms, but is not predictably related to the severity of extrarenal involvement HSP (IgAV) nephritis is generally mild in children (particularly young children), while adults are more likely to develop moderate to severe disease

Renal complications

There is a general correlation between the severity of the renal manifestations and the findings on renal biopsy

HenochSchönlein purpura (HSP) (IgA vasculitis)

A kidney biopsy is generally reserved for patients in whom the diagnosis is uncertain or who have more severe renal involvement. Light microscopy can show a wide spectrum of glomerular changes, ranging from isolated mesangial proliferation, focal and segmental proliferation, to severe crescentic glomerulonephritis.

Renal biopsy and urinalysis

On urine analysis: microscopic or macroscopic hematuria with or without red cell and other cellular casts or proteinuria

Specific treatment of HSP (IgAV) nephritis should be considered only in patients with severe renal dysfunctions

Treatment of renal involvment

The regimen consisting of pulse intravenous methylprednisolone (250 to 1000 mg per day for three days) followed by oral prednisone (1 mg/kg per day for three months) may be beneficial Other regimens that have been evaluated in children with crescentic nephritis include glucocorticoids and azathioprine Renal transplantation can be performed in patients who progress to end-stage renal disease

Fig. 14.12  Henoch-Schönlein purpura (HSP) (IgA vasculitis) [40]

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Table 14.3  Summary of renal involvement in different rheumatic diseases Rheumatic disease Systemic lupus erythematosus

Sjögren’s syndrome

Cryoglobulinemia Henoch-Schönlein purpura (HSP) (IgA vasculitis)

Polyarteritis Nodosa

Granulomatosis with polyangiitis GPA (Wegener’s) and microscopic polyangiitis (MPA) Eosinophilic granulomatosis with polyangiitis EGPA (Churg-Strauss) Rheumatoid arthritis (RA)

Mixed connective tissue disease (MCTD)

Scleroderma Ankylosing spondylitis

Renal complications  • Interstitial nephritis.  • Necrotizing vasculitis.  • Glomerulosclerosis.  • Chronic kidney disease.  • Nephritic syndrome.  • Rapidly progressive renal failure .  • Interstitial nephritis (may precede onset of sicca symptoms).  • Renal tubular acidosis (types I and II) (in 11%).  • Interstitial cystitis (rare).  • Glomerulonephritis (rare).  • Nephrolithiasis (rare).  • Membranoproliferative glomerulonephritis (60 to 80%).  • Hematuria with or without proteinuria.  • Isolated hematuria.  • Nephritic syndrome.  • Renal insufficiency.  • Hypertension.  • End-stage renal failure.  • Hypertension (common).  • Variable degrees of renal insufficiency.  • Rupture of renal arterial aneurysms can lead to perirenal hematomas.  • Multiple renal infarctions (in severe vasculitis) .  • Glomerulonephritis.  • Acute kidney injury with hematuria and cellular casts.  • Subnephrotic proteinuria.  • Rapidly progressive glomerulonephritis.  • Focal segmental glomerulonephritis common but renal failure rare.  • Rapidly progressive or acute renal insufficiency.  • Glomerulonephritis mainly with positive ANCA.  • Hypertension.  • Isolated proteinuria .  • Acute tubular necrosis related to nonsteroidal anti-inflammatory drug (NSAID) use.  • Secondary amyloidosis due to the chronic inflammation; it is now relatively rare in RA.  • Nephrotic syndrome secondary to membranous nephropathy.  • Necrotizing glomerulonephritis.  • Destructive inflammation within the walls of renal arteries.  • Glomerulonephritis.  • Renal vasculopathy.  • Malignant hypertension.  • Immune complex-­mediated nephritis.  • Interstitial nephropathy.  • Severe renal disease (rare) [4]  • Renal impairment usually mild.  • Scleroderma renal crisis rare (occurs in 1%–10%).  • Secondary renal amyloidosis.  • Immunoglobulin A (IgA) nephropathy.  • Membranoproliferative glomerulonephritis.  • Treatment-associated nephrotoxicity.  • Membranous glomerulonephritis (rare).  • Focal glomerulosclerosis (rare).  • Proliferative glomerulonephritis (rare) [5]

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Table 14.4  Renal side effects of commonly used drugs in rheumatic diseases Drugs NSAIDs

Cyclooxygenase-2 (COX-2) selective inhibitors Calcineurin inhibitors (cyclosporine and tacrolimus)

Methotrexate Sulfasalazine Leflunomide Gold Bisphosphonates

Penicillamine Azathioprine

Renal side effect - Acute tubular necrosis (ATN) - Acute interstitial nephritis (AIN) - Analgesic nephropathy: papillary necrosis and chronic interstitial nephritis - Minimal change disease - Membranous glomerulonephritis - Hyperkalemia - Hyponatremia - Salt and water retention - Renal tubular acidosis Acute kidney injury Salt and water retention Acute kidney injury Hyperkalemia Chronic interstitial fibrosis and tubular atrophy Hypophosphatemia Hypomagnesaemia Global glomerular sclerosis Focal segmental glomerulosclerosis Crystal-induced AKI (mainly with high dose IV) Interstitial nephritis (rare) Nephrotic syndrome (rare) Interstitial nephritis (rare) Membranous glomerulonephritis Acute tubular necrosis Focal segmental glomerulosclerosis Minimal change disease Membranous glomerulonephritis Minimal change disease Interstitial nephritis (rare)

14.9.6 Renal Side Effects of DMARDs and NSAIDs

Table14.4 summarized the renal side effects of commonly used drugs in rheumatic diseases.

Renal toxicity of disease-modifying antirheumatic drugs (DMARDs) and nonsteroidal anti-­ inflammatory drugs (NSAIDs) varies depending on the age and the kidney function of the patient. Side effects are commonly observed in elderly patients with compromised kidney function. Therefore, the use of NSAID should be avoided in patients with chronic kidney disease. Cyclosporine, gold, and penicillamine are associated with more serious renal side effects. Fortunately, gold and penicillamine are now very rarely used for the treatment of rheumatic diseases. Others like methotrexate, azathioprine, antimalarials, sulfasalazine, and leflunomide are safer with relatively less renal toxicity [35, 36].

Acknowledgments  The authors would like to thank Dr. Waleed Hafiz for his assistance in the development of this chapter.

References 1. Ellam TJ, El Nahas M. Proteinuria thresholds are irrational: a call for proteinuria indexing. Nephron Clin Pract. 2011;118(3):c217–24. 2. Wollin T, Laroche B, Psooy K. Canadian guidelines for the management of asymptomatic microscopic hematuria in adults. Can Urol Assoc J. 2009;3(1):77–80. 3. Grossfeld GD, et  al. Evaluation of asymptomatic microscopic hematuria in adults: the American urological association best practice policy--part I: definition, detection, prevalence, and etiology. Urology. 2001;57(4):599–603.

14  Renal System and Rheumatology 4. Ortega-Hernandez OD, Shoenfeld Y.  Mixed connective tissue disease: an overview of clinical manifestations, diagnosis and treatment. Best Pract Res Clin Rheumatol. 2012;26(1):61–72. 5. McVeigh CM, Cairns AP.  Diagnosis and management of ankylosing spondylitis. BMJ. 2006;333(7568):581–5. 6. Tang S, Lui SL, Lai KN. Pathogenesis of lupus nephritis: an update. Nephrology (Carlton). 2005;10(2):174–9. 7. Austin, H.A., 3rd, et al., Predicting renal outcomes in severe lupus nephritis: contributions of clinical and histologic data. Kidney Int, 1994. 45(2): p. 544–550. 8. Tisseverasinghe A, et  al. Association between serum total cholesterol level and renal outcome in systemic lupus erythematosus. Arthritis Rheum. 2006;54(7):2211–9. 9. Balow JE.  Clinical presentation and monitoring of lupus nephritis. Lupus. 2005;14(1):25–30. 10. Loizou S, et  al. Significance of anticardiolipin and anti-beta(2)-glycoprotein I antibodies in lupus nephritis. Rheumatology (Oxford). 2000;39(9):962–8. 11. Hahn BH, et al. American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis. Arthritis Care Res (Hoboken). 2012;64(6):797–808. 12. Mittal B, Rennke H, Singh AK.  The role of kidney biopsy in the management of lupus nephritis. Curr Opin Nephrol Hypertens. 2005;14(1):1–8. 13. KDIGO Clinical Practice Guideline for Glomerulonephritis. http://www.kidney-international. org, 2012. 2(2): p. 143. 14. Liu LL, et al. Efficacy and safety of mycophenolate mofetil versus cyclophosphamide for induction therapy of lupus nephritis: a meta-analysis of randomized controlled trials. Drugs. 2012;72(11):1521–33. 15. Duran-Barragan S, et  al. Angiotensin-converting enzyme inhibitors delay the occurrence of renal involvement and are associated with a decreased risk of disease activity in patients with systemic lupus erythematosus--results from LUMINA (LIX): a multiethnic US cohort. Rheumatology (Oxford). 2008;47(7):1093–6. 16. Pons-Estel GJ, et  al. Protective effect of hydroxychloroquine on renal damage in patients with lupus nephritis: LXV, data from a multiethnic US cohort. Arthritis Rheum. 2009;61(6):830–9. 17. Ramos-Casals M, Tzioufas AG, Font J.  Primary Sjögren’s syndrome: new clinical and therapeutic concepts. Ann Rheum Dis. 2005;64(3):347–54. 18. Aasarod K, et  al. Renal involvement in primary Sjogren's syndrome. QJM. 2000;93(5):297–304. 19. Bossini N, et al. Clinical and morphological features of kidney involvement in primary Sjogren's syndrome. Nephrol Dial Transplant. 2001;16(12):2328–36. 20. Maripuri S, et  al. Renal involvement in primary Sjogren's syndrome: a clinicopathologic study. Clin J Am Soc Nephrol. 2009;4(9):1423–31.

327 21. Ramos-Casals M, et al. Topical and systemic medications for the treatment of primary Sjogren's syndrome. Nat Rev Rheumatol. 2012;8(7):399–411. 22. Pertovaara M, Korpela M, Pasternack A.  Factors predictive of renal involvement in patients with primary Sjogren's syndrome. Clin Nephrol. 2001;56(1): 10–8. 23. Dammacco F, et al. The cryoglobulins: an overview. Eur J Clin Investig. 2001;31(7):628–38. 24. Denton CP, et al. Renal complications and scleroderma renal crisis. Rheumatology (Oxford). 2009;48(Suppl 3):iii32–5. 25. Traub YM, et  al. Hypertension and renal failure (scleroderma renal crisis) in progressive systemic sclerosis. Review of a 25-year experience with 68 cases. Medicine (Baltimore). 1983;62(6):335–52. 26. Steen VD, et al. Kidney disease other than renal crisis in patients with diffuse scleroderma. J Rheumatol. 2005;32(4):649–55. 27. Denton C, et al. Renal complications and scleroderma renal crisis. Rheumatology. 2009;48(suppl_3):iii32–5. 28. Sullivan PW, et  al. Influence of rheumatoid arthritis on employment, function, and productivity in a nationally representative sample in the United States. J Rheumatol. 2010;37(3):544–9. 29. Hickson LJ, et  al. Development of reduced kidney function in rheumatoid arthritis. Am J Kidney Dis. 2014;63(2):206–13. 30. Turesson C, et al. Occurrence of extraarticular disease manifestations is associated with excess mortality in a community based cohort of patients with rheumatoid arthritis. J Rheumatol. 2002;29(1):62–7. 31. Turesson C, et al. Rheumatoid factor and antibodies to cyclic citrullinated peptides are associated with severe extra-articular manifestations in rheumatoid arthritis. Ann Rheum Dis. 2007;66(1):59–64. 32. Gertz MA, Kyle RA. Secondary systemic amyloidosis: response and survival in 64 patients. Medicine (Baltimore). 1991;70(4):246–56. 33. Kronbichler A, Mayer G.  Renal involvement in autoimmune connective tissue diseases. BMC Med. 2013;11:95. 34. Agard C, et al. Microscopic polyangiitis and polyarteritis nodosa: how and when do they start? Arthritis Rheum. 2003;49(5):709–15. 35. Sinico RA, et  al. Renal involvement in Churg Strauss syndrome. Am J Kidney Dis. 2006;47(5): 770–9. 36. de Lind van Wijngaarden RA, et  al. Clinical and histologic determinants of renal outcome in ANCA-­ associated vasculitis: A prospective analysis of 100 patients with severe renal involvement. J Am Soc Nephrol. 2006;17(8):2264–74. 37. Hauer HA, et al. Determinants of outcome in ANCA-­ associated glomerulonephritis: a prospective clinico-­ histopathological analysis of 96 patients. Kidney Int. 2002;62(5):1732–42.

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S. Alobaidi et al. 40. Halling SF, Soderberg MP, Berg UB.  Henoch Schonlein nephritis: clinical findings related to renal function and morphology. Pediatr Nephrol. 2005;20(1):46–51.

Open Access  This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made. The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

Skin Manifestations of Rheumatological Diseases

15

Taha Habibullah, Ammar Habibullah, and Rehab Simsim

15.1 Introduction

15.2 Objectives

There are many rheumatic diseases presenting with skin manifestations. This could be the first presenting feature of a systemic rheumatic disease. In addition, some of these skin manifestations could be an indication of an active disease or a sign of a serious medical emergency. In this chapter the skin manifestations of common rheumatic diseases will be described. Particular focus will be placed on rheumatic diseases with polyarthritis. The differential diagnosis of erythema nodosum will be discussed as this condition is observed in several disorders with arthritis. There are many drugs used in rheumatology, some of them like allopurinol can lead to life-threatening dermatological conditions. A quick review on some of these conditions will be outlined. At the end of this chapter, the reader should be able to recognize different dermatological signs associated with patients with arthritis, discuss the differential diagnosis of erythema nodosum, and recognize life-threatening dermatological conditions.

• To identify the dermatological signs in patients presenting with polyarthritis. • To construct a diagnostic approach to patients presenting with erythema nodosum. • To recognize life-threatening dermatological conditions.

T. Habibullah (*) Al-Noor Specialist Hospital, Makkah, Saudi Arabia e-mail: [email protected]

15.3 Polyarthritis with Skin: (Diagram 15.1) 15.3.1  Rheumatoid Arthritis (RA) RA is a chronic inflammatory disorder that affects the joints and causes symmetrical arthritis. It usually involves extra-articular structures like the skin, eye, lung, heart, kidney, blood vessels, and bone marrow. The skin manifestations of RA will be discussed here.

15.3.2  Pyoderma Gangrenosum It presents as an inflammatory and ulcerative disorder of the skin. It’s an uncommon neutrophilic dermatosis. It presents commonly as an inflammatory papule or pustule that progresses to a painful ulcer; it may also present with bullous, vegetative, peristomal, and extracutaneous lesions.

A. Habibullah · R. Simsim King Abdullah Medical City, Makkah, Saudi Arabia © The Author(s) 2021 H. Almoallim, M. Cheikh (eds.), Skills in Rheumatology, https://doi.org/10.1007/978-981-15-8323-0_15

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15.3.3  Rheumatoid Vasculitis Inflammation of blood vessel is a central feature of RA, and it is considered as one of the primary events in the formation of rheumatoid nodule. Histologically it is characterized by mononuclear cell cuffing of postcapillary venule. It occurs in patients with long-standing joint-destructive RA.  It affects vessels from medium vessel to small arterioles; it leads to ischemia and necrosis to blood vessel “occlusion.”

15.3.4  Rheumatoid Nodule It is one of the most common cutaneous manifestations in RA.  The nodule is seen on pressure area such as olecranon process and many other areas in the body. It is firm, with size varies between 2 mm and 5 cm; non-tender and moveable in subcutaneous tissue; it could be painful, interfere with function, and may cause neuropathy [1]. Around 75% of patients with Felty’s syndrome have a nodule [1], and a vast majority of

patient with nodule have positive RF [2]. Patients with nodule are more likely to have vasculitis [3] (Figs. 15.1 and 15.2).

15.3.5  Skin Ulceration It may result from venous stasis, vasculitis, arterial insufficiency, and neutrophilic infiltration [4]. There are many cutaneous changes that occur in patients with RA such as granulomatous dermatitis and medication-induced skin changes, and also there are rare manifestations as linear bands or annular lesions, urticarial eruption, erythema elevatum diutinum, and dermal papule.

15.3.6  Systemic Lupus Erythematosus (SLE) The dermatological manifestations are the most common presentation of SLE in general. They involve the skin, mucous membranes, and hair.

Polyarthritis + Skin

ulceration

Scaly

lichen planus

heliotrope rash

Raynaud phenomenon

psoriatic plaques

malar rash

rheumatoid vasculitis

digital gangrene

guttate lesions

Necrolytic acral erythema

Gottron papules

cutaneous sclerosis

balanitis

photosensityvity

skin ulceration

Livedo reticularis

erythroderma

Prophyria cutanea tarda

poikiloderma

sclerodactyly

keratoderma

alopecia

pyoderma gangrenosum

subcutaneous nodules

Nail involvement

apthous ulcer

periungual telangiectasia

digital ulcers

Reactive arthritis

oral ulcerations

rehumatoid nodule

Vasculits

Psoriasis

leukocytoclastic vasculitis

calcinosis cutis.

hyperpigmentation

Discoid rash

RA

HCV

Facial erythema

Telangiectasia

SLE

Dermatomyositis

calcinosis cutis Systemic sclerosis

Fig. 15.1  The dermatological signs of patient presenting with polyarthritis. Source: Kelley’s textbook of rheumatology . available on:- www.medscape.com

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a

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b

Fig. 15.2  Periarticular skin-colored rheumatoid nodule

The new classification criteria of SLE contains acute cutaneous lupus erythematosus (ACLE) lesions, subacute cutaneous lupus erythematosus (SCLE), and chronic cutaneous lupus erythematosus as follows.

15.3.7  ACLE (Localized) 15.3.7.1 Malar Rash Characterized by erythematous butterfly-shaped rash over the cheeks and nasal bridge sparing the nasolabial folds, it can be flat or raised, painful, and lasting for days to weeks [5]. 15.3.7.2 Disseminated (Generalized) ACLE This lesion is characterized by erythematous to violaceous, scaly maculo-papular widespread exanthum symmetrically involves trunk and

extremities. Other nonspecific lesions can be seen, for example; subungual erythema, ulcers, pitting scars stubby hair cheilitis, periorbital edema, and diffuse telogen effluvium [5].

15.3.7.3 SCLE The clinical fissures of this type are characterized by circulating anti-Ro and anti-La antibodies and the HLA-B8 and HLA-DR3 haplotype. There are two variants that have been identified: annular variant and papulosquamous variant. The annular variant contains slightly raised erythemas with central clearing, while the papulosquamous variant consists of psoriasis-like or eczematous-like lesions. These two variants usually involve UV-exposed skin, including the lateral aspects of the face, the “V” of the neck, the upper ventral and dorsal part of the trunk, and the dorsolateral aspects of the forearms [5]. SCLE lesions commonly lead to hypopigmentation or depigmenta-

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tion and never lead to scarring. The systemic symptoms are mild like arthralgias and musculoskeletal complaints [5].

15.3.7.4 CCLE This is also called discoid CLE characterized by erythematous discoid plaque that becomes hyperkeratotic and finally leads to atrophy and scarring and can lead to dyspigmentation; it mainly involves the face, ears, and neck but may be widespread, and there are no relation of sun exposure. This lesion can affect the mucosal membranes including the lips, mucosal surfaces of the mouth, nasal membranes, conjunctivae, and genital mucosa. CCLE has several types like hypertrophic/verrucous lupus erythematosus, lupus erythematosus tumidus, lupus panniculitis/profundus, chilblain lupus erythematosus, and DLE–lichen planus overlap [5].

15.3.8  Others 15.3.8.1 Photosensitivity Macular rash present only after sun exposure may appear on the face, arms, or hands and persist for more than 1 day [6]. 15.3.8.2 Discoid Rash Erythematous patches with keratotic scaling over sun-exposed areas, plaque-like in character with follicular plugging and scarring [6] (Fig. 15.3). 15.3.8.3 Alopecia Mainly affects the temporal regions or creates a patchy pattern of hair loss [7] (Fig. 15.4). 15.3.8.4 Oral Ulcer It is an important manifestation of SLE; it occurs more than three times per year and is usually painless [7].

Fig. 15.3  Discoid lesions of lupus erythematosus. Show dyspigmentation, atrophy, and scarring

15.3.8.5 Systemic Sclerosis “Scleroderma” Scleroderma is a term used to describe a thickened skin. It may affect the skin and subjacent tissues, or it may be associated with systemic involvement [8]. 15.3.8.6 Raynaud Phenomenon Changes of the color of the digits due to abnormal vasoconstriction of digital arteries and cutaneous arterioles due to a local defect in normal vascular responses, (pallor , cyanosis and then redness). It is exaggerated by cold temperatures or emotional stress [9] (Fig. 15.5)

15.3.9  Telangiectasia It may develop anywhere within the body but mostly seen in perioral area, hands, and anterior chest. It’s small dilated blood vessels that locate beneath the dermis on skin (venule) (Fig. 15.6).

15  Skin Manifestations of Rheumatological Diseases

Fig. 15.4  Diffuse non-scarring alopecia

Fig. 15.5  Raynaud's phenomenon. Note the demarcation of color difference (pallor and cyanosis)

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15.3.10  Sclerodactyly It is a localized thickening and tightness of the skin of the fingers or toes. Sclerodactyly is commonly associated with atrophy of the underlying soft tissues. It is considered as a characteristic feature of scleroderma (Fig. 15.7).

15.3.11  Cutaneous Sclerosis It is the formation of scar tissue in the skin or in tissues around joints (Fig. 15.8). Note the tight and shiny appearance of skin.

15.3.12  Digital Ulcers With scleroderma, repeated episodes of spasm of the fingers (Raynaud’s) can cause pitted fingertip

Fig. 15.6 Telangiectasia

Fig. 15.7 Sclerodactyly

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scars, and in some people this results in fingertip ulcers [10].

15.3.13  Calcinosis Cutis It is mostly asymptomatic and developed gradually, in which amorphous, insoluble calcium salt deposits in the skin and subcutaneous tissue [11]. It’s usually firm, multiple, whitish dermal papules, plaques, nodules, or subcutaneous nodules. The lesion spontaneously ulcerated, and it may be tender and may restrict joint mobility. In severe cases it may cause cutaneous gangrene due to vascular calcification which diminishes the pulse. Hyperpigmentation and finger swelling are also considered as skin manifestations which occur in systemic sclerosis.

Fig. 15.8  Cutaneous sclerosis

15  Skin Manifestations of Rheumatological Diseases

15.4 Psoriasis 15.4.1  Scales (Fig. 15.9) 15.4.1.1 Nail Involvement Nail disease is more common in patients with psoriatic arthritis [12]. There is usually involvement of the nail matrix or nail bed. Nail abnormalities may include: beau lines, leukonychia, onycholysis, oil spots, subungual hyperkeratosis, splinter hemorrhages, spotted lunulae, transverse ridging, cracking of the free edge of the nail, and uniform nail pitting.

335

ally with a fine scale. It occurs primarily on the trunk and the proximal extremities; also it may have general distribution on the body [13] (Fig. 15.11).

15.4.1.4 Psoriatic Arthritis Psoriatic arthritis is one of the seronegative spondyloarthropathies which include ankylosing spondylitis and reactive arthritis. The prevalence of psoriatic arthritis among individuals with psoriasis is ranging from 7 to 48% [14–18]. There are several patterns of joint involvement in psoriatic arthritis patients [19]:

15.4.1.2 Erythroderma Patients commonly present with generalized erythema, then after the onset of erythema 2–6 weeks, scaling appears usually from flexural area. Pruritus commonly results in excoriations. If it persist for weeks, hair may shed, nails may become ridged, thickened and it may shed. Inflammation and edema in periorbital skin may occur resulting in ectropion (Fig. 15.10). 15.4.1.3 Guttate Lesion It is a clinical presentation that is characterized by a distinctive, acute eruption of small, droplike, 1–10 mm in diameter, salmon-pink papules, usu-

Fig. 15.10  Generalized erythroderma with scaly skin appearance

Fig. 15.9  Psoriatic plaques. Note the white to silvery scales over an erythematous base

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Fig. 15.11  Guttate psoriasis. Small discrete papules and plaques with fine scales

• Distal arthritis which involves distal interphalangeal (DIP) joints. • Asymmetric oligoarthritis. • Symmetric polyarthritis. • Arthritis mutilans, characterized by deforming and destructive arthritis. • Spondyloarthropathy which includes sacroiliitis and spondylitis.

15.4.2  Dermatomyositis (DM) 15.4.2.1 Gottron’s Papules They are symmetrical erythematous eruptions which involve the extensor aspects of the metacarpophalangeal (MCP) and interphalangeal (IP) joints and may involve the skin between them; they may be associated with scale and ulcer if the eruption was prominent [20] (Fig. 15.12).

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15.4.2.2 Heliotrope Eruption Erythematous lesion occurs on the upper eyelids and may be associated with eyelid edema (Fig. 15.13).

15.4.3  Facial Erythema This lesion can mimic the malar rash seen in SLE.  To easily differentiate between both of them, look at the nasolabial fold; if it is involved, then the rash is mainly due to DM; however, if it is not involved, then the rash is mainly due to SLE (Fig. 15.14).

Fig. 15.14  Facial erythema

15.4.4  Photodistributed Poikiloderma

Fig. 15.12  Gottron’s papules. Flat-topped papules over the proximal interphalangeal and metacarpophalangeal joints

Poikiloderma consists of both hyperpigmentation and hypopigmentation; it always occurs in upper chest, the V of the neck, and upper back (shawl sign); it may come as macular (nonpalpable) or papular erythema if it happens in early stages of cutaneous disease. It is usually associated with pruritus, and this is the difference between DM and photo-exacerbated eruption of lupus erythematosus. If the patient presents with poikiloderma on the lateral aspects of the thighs, this is now called Holster sign (Fig. 15.15).

15.4.5  Periungual Abnormalities These are characterized by erythematous lesion with vascular changes in the capillary nail beds which also may be associated with areas of dilatation and dropout and with periungual erythema [21].

15.4.6  Psoriasiform Changes in Scalp Fig. 15.13  Heliotrope sign. Note the pink to violaceous discoloration over eyelids and forehead

The scalp lesion in DM is diffuse, associated with prominent scaling and poikilodermatous changes.

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Fig. 15.15 Photodistributed poikiloderma. Note the hyperpigmentation, hypopigmentation, telangiectasia, and atrophy

It may be difficult to distinguish from seborrheic dermatitis and psoriasis. It happens usually as a result of severe burning, pruritus, or sleep disturbance.

with glucocorticoids and immunosuppressive therapy; this lesion can be seen in other diseases like systemic sclerosis and SLE but more common with DM [22, 23].

15.4.7  Calcinosis Cutis

15.4.8  Reactive Arthritis

It is more common in juvenile DM than adult DM.  It means deposition of calcium within the skin. It is associated with a delay in treatment

15.4.8.1 Circinate Balanitis It is an asymptomatic genital lesion characterized by shallow ulcers in the penis [24].

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15.4.8.2 Keratoderma Hyperkeratotic skin rashes involve soles and palms [24] (Fig. 15.16).

15.4.9  Hepatitis C Virus (HCV) 15.4.9.1 Porphyria Cutanea Tarda It is a skin lesion strongly associated with HCV and characterized by photosensitivity, bruising skin, fragility, facial hirsutism, and vesicles or bullae that can become hemorrhagic. It is a skin disease caused by a reduction of hepatic uroporphyrinogen decarboxylase activity [25]. 15.4.9.2 Leukocytoclastic Vasculitis This lesion is usually associated with palpable purpura and petechiae that usually involve the lower extremities and may happen in conjunction with essential mixed cryoglobulinemia; in skin biopsy, there is dermal blood vessel destruction associated with a neutrophilic infiltration in and around the vessel wall (Fig. 15.17) [26].

15.4.10  Lichen Planus It involves mucus membranes, hair, and nails characterized by flat-topped, violaceous, pruritic papules with a generalized distribution. In skin biopsy, there is a dense lymphocytic infiltration in the upper dermis [27, 28] (Fig. 15.18).

Fig. 15.17  Leukocytoclastic vasculitis. Note the scattered palpable purpura and hemorrhagic macules

15.4.11  Necrolytic Acral Erythema This lesion is pruritic and characterized by sharply marginated, erythematous to hyperpigmented plaques with variable scale and erosion which involves the lower extremities (Fig. 15.19) [29].

15.4.12  Polyarteritis Nodosa 15.4.12.1 Livedo Reticularis It is characterized by tenderness and it does not blanch with active pressure [30–32]. 15.4.12.2 Ulcerations It usually involves the lower extremities [30–32].

15.4.13  Digital Ischemia It may be associated with splinter hemorrhages and gangrene [30–32].

15.5 Sarcoidosis

Fig. 15.16 Keratoderma blennorrhagicum. Note the thick yellow scales on the soles

It is a granulomatous disease and defined as presence of non-caseating granulomas in different tissues and organs such as lymph nodes, eyes, joints, brain, kidneys, lung, and skin. The signs that appear with sarcoidosis are as follows.

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a

b

Fig. 15.18  Flat-topped, polygonal, and violaceous papules of lichen planus

15.5.1  Erythema Nodosum

15.5.2  Papular Sarcoidosis

It is the most common nonspecific lesion of sarcoidosis and characterized by inflammatory, tender, erythematous, subcutaneous plaques and nodules in the anterior tibial areas. The patient can present with low-grade fever, arthritis, and lower extremity edema (Fig. 15.20) [32].

It is the most common specific lesion characterized by numerous non-scaly, skin-colored, yellow-­ brown, red-brown, violaceous, or hypopigmented 1 to 10  mm papules, and the papules can demonstrate a slight central ­ depression. The most common site is the face,

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with a predilection for the eyelids and nasolabial folds [33].

15.5.3  Nodular Sarcoidosis Subcutaneous sarcoidosis or nodular sarcoidosis, all these terms describe the nodule arising from subcutaneous tissue [32]; it is one of the most common lesions in sarcoidosis, and it results from large collections of sarcoidal granulomas in the dermis or subcutaneous tissue characterized

Fig. 15.19  Necrolytic acral erythema

Fig. 15.20 Erythema nodosum

Erythema Nodosum with

Pyoderma gangrenosum

Papulopustular eruptions

Papular sarcoidosis

Arthritis

Erythema multiforme

Subcutaneous sarcoidosis

Oral ulcer

Anceiform lesions

Maculopapular sarcoidosis

Inflammatory bowel disease

Ulcers (oral, genital)

Plaque sarcoidosis

folliculitis like rash

Lupus pernio

Thrombophlebitis

Hypopigmented sarcoidosis

Pyoderma gangrenosum

Atrophic and ulcerative

Arthritis

Sarcoidosis

positive pathergy reaction at injection site

Behcet Syndrome

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as asymptomatic or mildly tender, flesh-colored, erythematous, violaceous, and hyperpigmented. The upper extremities are the most common site of nodular sarcoidosis [34]. It can be single or multiple, and its size could be about 1 and 2 cm in diameter. The differential diagnosis of subcutaneous sarcoidosis includes lipomas, cysts, cutaneous manifestations of lymphoproliferative malignancies, subcutaneous granuloma annulare, foreign body, or granulomas [35, 36].

15.5.4  Maculopapular Sarcoidosis This lesion is characterized by raised papules that are often around 1 mm in diameter, slightly tender, pruritic, slightly hyperpigmented patches, red, brown, or violaceous in color [37]; the most common sites are facial and eyelid areas, and it may involve mucous membranes, neck, trunk, or extremities [32].

15.5.5  Plaque Sarcoidosis This lesion is characterized by oval or annular shaped, indurated, different color such as flesh-­ colored, erythematous or brown rash that may have scale at the end stage. The most common sites involved are the arms, shoulders, back, and buttocks; it has common features with psoriasis, lichen planus, discoid lupus, granuloma annulare, cutaneous T cell lymphoma, secondary syphilis, and Kaposi’s sarcoma [36].

15.5.6  Lupus Pernio This lesion is characterized by erythematous, indurated papules, plaques, or nodules [38]; the most common sites involved are the face, nasal tip, alar rim, and cheeks, and it may involve ears and lips [39]. If this lesion is not treated, it will progress rapidly and increase in thickness, size, and induration. After the lesion is resolved, it will leave scar [37]. This lesion is associated more

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with extracutaneous manifestations such as respiratory tract involvement and lytic and cystic bone lesions [40].

15.5.7  Hypopigmented Sarcoidosis It affects mostly dark-skinned persons of African descent, and the lesion is characterized by round to oval, hypopigmented, well-demarcated patches and may have raised plaques [33, 41].

15.5.8  Atrophic and Ulcerative Sarcoidosis This lesion is a combined lesion meaning it is involved with atrophic and ulcerated lesions, which are characterized by depressed plaques not elevated [42]; this lesion is associated with other mucocutaneous manifestations of sarcoidosis. The ulcerative lesion is more common in women and black patients [43].

15.6 Rheumatic Fever Acute rheumatic fever is a non-suppurative sequela that occurs after 2–3 weeks of group A streptococcus and pharyngitis. It mostly affects children aged 5 to 15 years. This disease is characterized by arthritis, carditis, chorea, erythema marginatum, and subcutaneous nodules. The damage to the cardiac valve is chronic and it may progress [44]. To make a diagnosis of rheumatic fever, there is a special criterion called Jones Criteria, which involves major and minor manifestations which are as follows. The major manifestations: • • • • •

Arthritis. Carditis. Chorea. Erythema marginatum. Subcutaneous nodules.

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The minor manifestations: • Arthralgia. • Fever. • Elevated acute phase reactants (erythrocyte sedimentation rate [ESR], C-reactive protein [CRP]). • Prolonged PR interval. In this chapter we will talk only about the rheumatological and dermatological manifestations, which are as follows.

15.6.1  Arthritis It is the early symptom of rheumatic fever. The classical history of arthritis involves migratory polyarthritis within days to a week. The meaning of migratory is “it affects the joint then migrates to the other joint”; the most common joints involved are knees, elbows, and wrists [36]; the patient will complain of limitation in his movement because of the severity of the joint pain. The inflammation of each joint lasts no more than 1 week and the signs of inflammation are usually present [45].

15.6.2  Erythema Marginatum This lesion appears early in the course of the rheumatic fever characterized by an evanescent, pink or faintly red, non-pruritic rash; the outer edge is sharp and the inner is diffuse; it has continuous margins and sometimes has a ring shape. It usually affects the trunk and may affect the limbs, but it is unlikely to affect the face [46]. The course of this lesion is intermittent meaning that it appears, disappears, and then reappears in a matter of hours [47].

15.6.3  Subcutaneous Nodules This lesion is characterized by symmetrical, firm, painless lesions ranging from a few milli-

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meters to 2 cm in size, and the average number of nodules is about three to four, and it has noninflamed skin above it. The nodules present over the bony surface or prominence or near tendons. This lesion appears 1 week after the disease and is associated with sever carditis lasting no more than 1 month. We can distinguish rheumatic fever nodules from rheumatic arthritis nodules as the rheumatic fever nodules are smaller and more short-lived than the nodules of rheumatoid arthritis and almost involve the olecranon, while rheumatoid nodules are usually found 3 to 4  cm distally; finally all of them involve the elbows [48].

15.7 Behçet’s Disease Behçet’s disease is a complex, multi-systemic disease that involves the mucocutaneous, ocular, cardiovascular, renal, gastrointestinal, pulmonary, urologic, and central nervous systems, the joints, blood vessels, and lungs. Men are more commonly affected by this disease than women, and it is more common in the third decade of life, but it can occur at any age. Signs and symptoms of this disease may precede the onset of the mucosal membrane ulcerations by 6 months to 5 years, and prior to the onset of the disease, the patient experiences generalized and various symptoms. In patients with Behçet’s disease, a variety of cutaneous changes appear on them [49].

15.7.1  Erythema Nodosum-like Lesion It is red to violet and painful subcutaneous nodule. It occurs on the extremities especially the lower extremities; also it can present on the face, neck, and buttocks. It resolves spontaneously or it may ulcerate leaving a scar and hyperpigmentation area.

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15.7.2  Acneiform Lesion It may be more common in those with associated arthritis [50]. It consists of papules and pustules that are difficult to distinguish from ordinary acne [51].

15.7.3  Folliculitis-like Rash It distributes on the back, face, neck, chest, and hairline of patients. It resembles acne vulgaris.

T. Habibullah et al. Table 15.1 Oral examination

ulcer

description

on

physical

Oral ulcer description on physical exam More painful More Appear frequent singly or in More crops extensive Located Evolve Lesions can Have a anywhere quickly central, be shallow in the oral from a yellowish, or deep cavity necrotic base pinpoint (2–30 mm flat ulcer in diameter) and a punched-out, to a large clean margin sore Subside without leaving Persist for 1–2 weeks scars

15.7.4  Papulopustular Eruptions Pustular skin lesions are often not sterile and may contain Staphylococcus aureus and Prevotella spp. [52].

15.7.5  Erythema Multiforme-like Lesions 15.7.6  Superficial Thrombophlebitis It is a migratory superficial thrombophlebitis of the skin. It may be associated with deep vein thrombosis that causes lower extremities edema.

15.7.7  Ulcers (Oral, Genital) During physical exam: –– Oral ulcer: difficult to distinguish from common aphthae (Table 15.1). –– The most common sites are the tongue, lips, buccal mucosa, and gingiva; the tonsils, palate, and pharynx are less common sites. The interval between recurrences ranges from weeks to months. –– Genital ulcers: recurrent and painful, and it may cause scarring.

15.7.8  Pyoderma Gangrenosum It is an ulcerative cutaneous condition starting from a small, red papule or pustule and then changing into an ulcerative lesion.

15.7.9  P  ositive Pathergy Reaction at Injection Site Nonspecific inflammatory reaction to scratches and intradermal saline injection is a common and specific manifestation to these lesions.

15.7.10  Arthritis During an exacerbation of disease, a non-erosive, asymmetrical arthritis occurs in about 50% of patients with this disease. It involves large and medium joints (wrist, knee, and ankle). Also for the patient with Behçet’s disease, experiencing myalgias and migratory arthralgias without overt arthritis is common. On the other hand, arthritis occurs in about 50% of patients with Behçet’s disease [53]. There are also genital, ocular, gastrointestinal, joint, and neurologic manifestations.

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15.8 Inflammatory Bowel Disease Inflammatory bowel disease (IBD) includes two major disorders, which are ulcerative colitis and Crohn’s disease. This group of diseases cause many extraintestinal manifestations including eye, skin, joint, renal, and urologic conditions. In this chapter we will talk about skin and the musculoskeletal manifestations of IBD.  The most common skin lesions presenting with IBD are erythema nodosum and pyoderma gangrenosum and other less common lesions such as Sweet syndrome, necrotizing cutaneous vasculitis, and psoriasis.

15.8.1  Erythema Nodosum (EN) This lesion is equally present in ulcerative colitis and Crohn’s disease, and it is characterized by raised, tender, red or violet subcutaneous nodules, which are around 1 to 5 cm in diameter. The most common sites involved are the extensor surfaces of the extremities, specifically over the anterior tibial area. The presence of erythema nodosum reflects the activity of the intestinal disease and usually disappears by management of intestinal manifestations. Also this lesion is diagnosed clinically, and if we take a biopsy, it will show focal panniculitis, which is rarely done [54].

15.8.2  Pyoderma Gangrenosum This lesion is less common than EN, and it has a severe course because of its persistence, and it is an uncomfortable lesion preceded by trauma to the skin and initially appears as single or multiple erythematous papules or pustules [55]. The most common site involved is the legs, but it can appear at any site including

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abdomen and at the site of surgical scars or at the stoma after colectomy. It may form deep ulceration that contains purulent material by subsequent necrosis of the dermis, and usually the culture of the purulent material is sterile. Pyoderma gangrenosum reflects the activity of IBD disease, and it needs a course of high-dose glucocorticoids over several weeks of treatment [56].

15.8.3  Oral Ulcer It is a common manifestation in patients with IBD, especially patients with Crohn’s disease.

15.8.4  Musculoskeletal Manifestations The musculoskeletal manifestations of IBD are considered the most common extra-intestinal manifestation, and they include; non-destructive peripheral arthritis and axial arthritis, other less common musculoskeletal manifestations are osteoporosis, osteopenia, and osteonecrosis.

15.8.5  Arthritis The joints that are involved are the spine, sacroiliac joints, and appendicular joints; there are two types of peripheral arthritis: type 1 is acute and remitting and type 2 is a chronic problem and causes frequent relapses; other joint pain can result from complications of IBD such as bacterial infection of the sacroiliac or peripheral joints or as adverse effects from chronic use of glucocorticoid such as osteonecrosis, and those complications must be distinguished from sterile inflammation [57].

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15.9 Severe and Life-Threatening Conditions (Fig. 15.21)

separation of significant areas of skin at the dermal-­ epidermal junction, producing the appearance of scalded skin [59]. We can classify this disease simply into as follows:

15.10 Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN)

–– Stevens-Johnson syndrome (a minor form of toxic epidermal necrolysis): less than 10% body surface area (BSA) detachment. –– Overlapping Stevens-Johnson syndrome/ toxic epidermal necrolysis: detachment of 10–30% of the BSA.

They are rare, acute immune complex medited hypersensitive and life that are nearly always drug-related. Allopurinol is the most common cause [58]. They are a consequence of extensive keratinocyte cell death that results in the

Toxic epidermal necrolysis: detachment of more than 30% of the BSA.

Fig. 15.21  Severe and life-threatening conditions

Severe and life threatening conditions

Rash

Livedo reticularis

Erythema

Bullous lesion

Raynaud’s phenomenon

Exfoliation and scales

Urticarial lesions

Pyoderma gangerenousu m-like lesion

Pruritus

Erythema

Nailfold ulcer

Skin pain

Palpable purpura

Splinter hemorrhage

Dyspigmentation

Edema “face tongue”

Cutaneous necrosis

Palmoplanter keratoderma

Sloughing of skin

Superficial thrombophlebitis

Nail changes

Blistering

Purpura

Diffuse nonscarring alopecia

catastrophic antiphospholipi d syndrome

Exfoliative erythroderma

Skin Ulceration Skin Necrosis

Toxic Epidermal Necrolysis

Steven Johnson Syndrome

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The initial symptoms of Stevens-Johnson syndrome and toxic epidermal necrolysis that precede cutaneous manifestations by 1 to 3 days are fever, productive cough with thick purulent sputum, pain on swallowing, headache, arthralgia, and malaise. A patient with SJS and TEN may complain of a rash, which appears first on the trunk, spreading to the neck, face, and proximal upper extremities. The following points are characteristic of cutaneous lesions:

15.10.4  Erythema

15.10.1  Rash

15.10.6.1 Sloughing of Skin –– Skin looks like wet cigarette paper. –– Skin ulceration. –– Skin necrosis. –– Nikolsky sign: it should be sought by exerting tangential mechanical pressure with a finger on several erythematous zones and considered positive if dermal-epidermal cleavage is induced (Fig. 15.25).

It first appears as macules and then develops into papules, vesicles, bullae, urticarial plaques, or confluent erythema (erythroderma) (Fig. 15.22).

15.10.2  Bullous Lesions It appears as flaccid blisters and may rupture leaving denuded skin (Fig. 15.23).

15.10.3  U  rticarial Lesions (Not Pruritic) It may be edematous, erythematous to pale area involving the dermis and epidermis (Fig. 15.24).

Erythema and erosions of the buccal, ocular, and genital mucosae are present in more than 90% of patients.

15.10.5  Palpable Purpura 15.10.6  Edema (Face, Tongue)

15.11 Erythroderma Exfoliation More than 90% of body surface areas are involved by generalized redness and scaling of the skin due to generalization of pre-existing dermatoses (such as psoriasis or atopic dermatitis), drug reactions, or cutaneous T-cell lymphoma (CTCL) [60]. The clinical features are as follows:

15.11.1  Erythema 15.11.1.1 E  xfoliation and Scales (2–6 Days after Erythema) There is variation in the size and the color of the scales. In acute phases, scales are usually large and crusted while in chronic states are smaller and drier. Occasionally, the cause of the erythroderma is suggested by the character of the scale:

Fig. 15.22  Dusky to violaceous rash of toxic epidermal necrolysis

• Fine scale in atopic dermatitis dermatophytosis. • Bran-like in seborrheic dermatitis. • Crusted in pemphigus foliaceus. • Exfoliative in drug reactions.

or

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Fig. 15.23  Flaccid bullae with detachment of necrolytic epidermis

Fig. 15.24  Urticarial plaques (wheals)

Fig. 15.25  Nikolsky sign

15  Skin Manifestations of Rheumatological Diseases

15.11.2  Pruritus Approximately 90% of patients complain from it, so it is the most frequent complaint. Thickness of the skin and areas of lichenification are seen in one-third of cases due to itching.

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• Tachycardia. • Splenomegaly is rarely seen and occurs most often in association with lymphoma.

15.11.9  Complications

15.11.4  Dyspigmentation

• Multiple seborrheic keratosis. • Cutaneous infection with Staphylococcus aureus. • Bilateral ectropion. • Purulent conjunctivitis. • Risk of cardiac failure. • Anemia.

Hyperpigmentation area (45%) observed more frequently than hypo- or depigmentation (20%).

15.12 Gonococcal Arthritis

15.11.3  Pain Most patients complain of severe skin pain.

15.11.5  Palmoplantar Keratoderma Hyperkeratosis of the palms and soles. Approximately 30% of erythrodermic patients present with it.

15.11.6  Nail Changes They are related to the underlying cause of erythroderma, for example, pit in psoriasis or horizontal ridging in dermatitis. Most often “shiny” nails are observed, but discoloration, brittleness, dullness, subungual hyperkeratosis, Beau’s lines, paronychia, and splinter hemorrhages can be seen.

15.11.7  Diffuse Non-scarring Alopecia It appears in 20% of patients with chronic erythroderma.

15.11.8  Systemic Manifestation • Generalized peripheral lymphadenopathy. • Pedal or pretibial edema. • Facial edema.

Considered as the most common form of septic arthritis in the United States and caused by gram-­ negative diplococcus Neisseria gonorrhoeae. It is composed of two forms: –– Bacteremic form (arthritis-dermatitis syndrome). –– Septic arthritis form (localized to the joint) [58] Bacteremic form (arthritis-dermatitis syndrome) • Migratory arthralgias and arthritis: It presents as: –– Polyarticular. –– Asymmetric. –– Upper extremities involvement more than lower extremities. –– The most commonly affected joints are wrists, elbows, knees, and ankles. –– It may evolve into a septic arthritis. • Tenosynovitis: An inflammation that involves the tendon and its sheath; it is almost always asymmetrical and commonly over the dorsum of the wrist and hands. Also, it can affect the ankle, knee, and metacarpophalangeal joints [60]. • Dermatitis: Around 40–70% of patients with bacteremic form are affected.

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It presents as: Tiny maculopapular, pustular, or vesicular lesions on an erythematous base. Painless and non-pruritic lesions. The lesion’s center may become necrotic or hemorrhagic. The lesions may rarely resemble erythema nodosum or erythema multiforme [60].

Other presentations may include: • Fever, rarely higher than 39 °C. • Fitz-Hugh-Curtis syndrome (gonococcal perihepatitis). • Sepsis with Waterhouse-Friderichsen syndrome. • Gonococcal endocarditis (rare in the antibiotic era). • Gonococcal meningitis (very rare in the antibiotic era). Septic arthritis form: It presents as an acute inflammation to the joints with signs of: • • • • •

Joint effusion. Warmth. Tenderness. Reduced range of motion. Marked erythema.

One form of complication is permanent joint damage. Other complications are pericarditis, perihepatitis, pyomyositis, glomerulonephritis, meningitis, endocarditis, and osteomyelitis [58].

Abbreviations RA PND HCV SLE ACLE SCLE

Rheumatoid arthritis Paraneoplastic neurological disorders Hepatitis C virus Systemic lupus erythematosus Acute cutaneous lupus erythematosus Subacute cutaneous lupus erythematosus CCLE Chronic cutaneous lupus erythematosus DLE Discoid lupus erythematosus

DIP Distal interphalangeal joint DM Dermatomyositis CTCL Cutaneous T-cell lymphoma ESR Erythrocyte sedimentation rate CRP C-reactive protein IBD Inflammatory bowel disease EN Erythema nodosum SJS Stevens-Johnson syndrome TEN Toxic epidermal necrolysis BSA Body surface area

References 1. Garcia-Patos V.  Rheumatoid nodule. Semin Cutan Med Surg. 2007;26(2):100–7. https://doi. org/10.1016/j.sder.2007.02.007. 2. Sayah A, English JC 3rd. Rheumatoid arthritis: a review of the cutaneous manifestations. J Am Acad Dermatol. 2005;53(2):191–209; quiz 210-192. https:// doi.org/10.1016/j.jaad.2004.07.023. 3. Turesson C, McClelland RL, Christianson T, Matteson E.  Clustering of extraarticular manifestations in patients with rheumatoid arthritis. J Rheumatol. 2008;35:179–80. 4. Oien RF, Hakansson A, Hansen BU.  Leg ulcers in patients with rheumatoid arthritis--a prospective study of aetiology, wound healing and pain reduction after pinch grafting. Rheumatology (Oxford). 2001;40(7):816–20. 5. Böhm M, Luger TA Skin in Rheumatic disease. In GS Firestein, RC Budd, SE Gabriel, IB Mcinnes & JR O'Dell (Eds.), Kelley's Textbook Of Rheumatology (9th ed.) 6. Callen JP.  Systemic lupus erythematosus in patients with chronic cutaneous (discoid) lupus erythematosus. Clinical and laboratory findings in seventeen patients. J Am Acad Dermatol. 1985;12(2 Pt 1):278–88. 7. Healy E, Kieran E, Rogers S.  Cutaneous lupus erythematosus--a study of clinical and laboratory prognostic factors in 65 patients. Ir J Med Sci. 1995;164(2):113–5. 8. LeRoy EC, Black C, Fleischmajer R, Jablonska S, Krieg T, Medsger TA Jr, et al. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol. 1988;15(2):202–5. 9. Wigley FM.  Clinical practice. Raynaud's phenomenon. N Engl J Med. 2002;347(13):1001–8. https:// doi.org/10.1056/NEJMcp013013. 10. Reiter N, El-Shabrawi L, Leinweber B, Berghold A, Aberer E. Calcinosis cutis: part I. diagnostic pathway. J Am Acad Dermatol. 2011;65(1):1–12.; quiz 13-14. https://doi.org/10.1016/j.jaad.2010.08.038. 11. Klaassen KM, van de Kerkhof PC, Pasch MC.  Nail psoriasis: a questionnaire-based survey. Br J Dermatol. 2013;169(2):314–9. https://doi.org/10.1111/ bjd.12354.

15  Skin Manifestations of Rheumatological Diseases 12. Baker BS, Owles AV, Fry L. A possible role for vaccination in the treatment of psoriasis? G Ital Dermatol Venereol. 2008;143(2):105–17. 13. Gelfand JM, Gladman DD, Mease PJ, Smith N, Margolis DJ, Nijsten T, et  al. Epidemiology of psoriatic arthritis in the population of the United States. J Am Acad Dermatol. 2005;53(4):573. https://doi. org/10.1016/j.jaad.2005.03.046. 14. Reich K, Kruger K, Mossner R, Augustin M.  Epidemiology and clinical pattern of psoriatic arthritis in Germany: a prospective interdisciplinary epidemiological study of 1511 patients with plaque-­ type psoriasis. Br J Dermatol. 2009;160(5):1040–7. https://doi.org/10.1111/j.1365-2133.2008.09023.x. 15. Radtke MA, Reich K, Blome C, Rustenbach S, Augustin M. Prevalence and clinical features of psoriatic arthritis and joint complaints in 2009 patients with psoriasis: results of a German national survey. J Eur Acad Dermatol Venereol. 2009;23(6):683–91. https://doi.org/10.1111/j.1468-3083.2009.03159.x. 16. Ibrahim G, Waxman R, Helliwell PS. The prevalence of psoriatic arthritis in people with psoriasis. Arthritis Rheum. 2009;61(10):1373–8. https://doi.org/10.1002/ art.24608. 17. Mease PJ, Gladman DD, Papp KA, Khraishi MM, Thaci D, Behrens F, et al. Prevalence of rheumatologist-­ diagnosed psoriatic arthritis in patients with psoriasis in European/North American dermatology clinics. J Am Acad Dermatol. 2013;69(5):729–35. https://doi. org/10.1016/j.jaad.2013.07.023. 18. Garg A, Gladman D.  Recognizing psoriatic arthritis in the dermatology clinic. J Am Acad Dermatol. 2010;63(5):733–48; quiz 749-750. https://doi. org/10.1016/j.jaad.2010.02.061. 19. Dugan EM, Huber AM, Miller FW, Rider LG.  Photoessay of the cutaneous manifestations of the idiopathic inflammatory myopathies. Dermatol Online J. 2009;15(2):1. 20. Smith RL, Sundberg J, Shamiyah E, Dyer A, Pachman LM.  Skin involvement in juvenile dermatomyositis is associated with loss of end row nailfold capillary loops. J Rheumatol. 2004;31(8):1644–9. 21. Gunawardena H, Wedderburn LR, Chinoy H, Betteridge ZE, North J, Ollier WE, et al. Autoantibodies to a 140kd protein in juvenile dermatomyositis are associated with calcinosis. Arthritis Rheum. 2009;60(6):1807– 14. https://doi.org/10.1002/art.24547. 22. Ceribelli A, Fredi M, Taraborelli M, Cavazzana I, Franceschini F, Quinzanini M, et al. Anti-MJ/NXP-2 autoantibody specificity in a cohort of adult Italian patients with polymyositis/dermatomyositis. Arthritis Res Ther. 2012;14(2):R97. https://doi.org/10.1186/ ar3822. 23. Lee LA, Werth VP The skin and rheumatic diseases. In GS Firestein, RC Budd, SE Gabriel, IB Mcinnes & JR O'Dell (Eds.), Kelley's Textbook Of Rheumatology (9th ed.). 24. Gisbert JP, Garcia-Buey L, Pajares JM, Moreno-­ Otero R. Prevalence of hepatitis C virus infection in

351 porphyria cutanea tarda: systematic review and meta-­ analysis. J Hepatol. 2003;39(4):620–7. 25. David WS, Peine C, Schlesinger P, Smith SA.  Nonsystemic vasculitic mononeuropathy multiplex, cryoglobulinemia, and hepatitis C. Muscle Nerve. 1996;19(12):1596–602. https://doi.org/10.1002/ (SICI)1097-4598(199612)19:123.0.CO;2-5. 26. Pilli M, Penna A, Zerbini A, Vescovi P, Manfredi M, Negro F, et  al. Oral lichen planus pathogenesis: a role for the HCV-specific cellular immune response. Hepatology. 2002;36(6):1446–52. https://doi. org/10.1053/jhep.2002.37199. 27. Protzer U, Ochsendorf FR, Leopolder-Ochsendorf A, Holtermuller KH. Exacerbation of lichen planus during interferon alfa-2a therapy for chronic active hepatitis C. Gastroenterology. 1993;104(3):903–5. 28. Abdallah MA, Ghozzi MY, Monib HA, Hafez AM, Hiatt KM, Smoller BR, Horn TD.  Necrolytic acral erythema: a cutaneous sign of hepatitis C virus infection. J Am Acad Dermatol. 2005;53(2):247–51. https://doi.org/10.1016/j.jaad.2005.04.049. 29. Pagnoux C, Seror R, Henegar C, Mahr A, Cohen P, Le Guern V, et al. Clinical features and outcomes in 348 patients with polyarteritis nodosa: a systematic retrospective study of patients diagnosed between 1963 and 2005 and entered into the French Vasculitis study group database. Arthritis Rheum. 2010;62(2):616–26. https://doi.org/10.1002/art.27240. 30. Gibson LE, Su WP. Cutaneous vasculitis. Rheum Dis Clin N Am. 1995;21(4):1097–113. 31. Karlsberg PL, Lee WM, Casey DL, Cockerell CJ, Cruz PD Jr. Cutaneous vasculitis and rheumatoid factor positivity as presenting signs of hepatitis C virus-­ induced mixed cryoglobulinemia. Arch Dermatol. 1995;131(10):1119–23. 32. Yanardag H, Pamuk ON, Karayel T.  Cutaneous involvement in sarcoidosis: analysis of the features in 170 patients. Respir Med. 2003;97(8):978–82. 33. Elgart ML.  Cutaneous sarcoidosis: definitions and types of lesions. Clin Dermatol. 1986;4(4):35–45. 34. Ben Jennet S, Benmously R, Chaabane S, Fenniche S, Marrak H, Mohammed Z, Mokhtar I. Cutaneous sarcoidosis through a hospital series of 28 cases. Tunis Med. 2008;86(5):447–50. 35. Ahmed I, Harshad SR.  Subcutaneous sarcoidosis: is it a specific subset of cutaneous sarcoidosis frequently associated with systemic disease? J Am Acad Dermatol. 2006;54(1):55–60. https://doi. org/10.1016/j.jaad.2005.10.001. 36. Lodha S, Sanchez M, Prystowsky S.  Sarcoidosis of the skin: a review for the pulmonologist. Chest. 2009;136(2):583–96. https://doi.org/10.1378/ chest.08-1527. 37. Mangas C, Fernandez-Figueras MT, Fite E, Fernandez-­ Chico N, Sabat M, Ferrandiz C. Clinical spectrum and histological analysis of 32 cases of specific cutaneous sarcoidosis. J Cutan Pathol. 2006;33(12):772–7. https://doi.org/10.1111/j.1600-0560.2006.00563.x.

352 38. Veien NK, Stahl D, Brodthagen H. Cutaneous sarcoidosis in Caucasians. J Am Acad Dermatol. 1987;16(3 Pt 1):534–40. 39. Mana J, Marcoval J, Graells J, Salazar A, Peyri J, Pujol R.  Cutaneous involvement in sarcoidosis. Relationship to systemic disease. Arch Dermatol. 1997;133(7):882–8. 40. Jorizzo JL, Koufman JA, Thompson JN, White WL, Shar GG, Schreiner DJ.  Sarcoidosis of the upper respiratory tract in patients with nasal rim lesions: a pilot study. J Am Acad Dermatol. 1990;22(3):439–43. 41. Terunuma A, Watabe A, Kato T, Tagami H. Coexistence of vitiligo and sarcoidosis in a patient with circulating autoantibodies. Int J Dermatol. 2000;39:551–3. 42. Albertini JG, Tyler W, Miller OF. Ulcerative sarcoidosis. Case report and review of the literature. Arch Dermatol. 1997;133(2):215–9. 43. Yoo SS, Mimouni D, Nikolskaia OV, Kouba DJ, Sauder DN, Nousari CH.  Clinicopathologic features of ulcerative-atrophic sarcoidosis. Int J Dermatol. 2004;43(2):108–12. 44. Guidelines for the diagnosis of rheumatic fever. Jones Criteria. Update. Special writing Group of the Committee on rheumatic fever, endocarditis, and Kawasaki disease of the council on cardiovascular disease in the young of the American Heart Association. (1992). JAMA. 1992;268(15):2069–73. 45. Wallace MR, Garst PD, Papadimos TJ, Oldfield EC 3rd. The return of acute rheumatic fever in young adults. JAMA. 1989;262(18):2557–61. 46. Burke JB.  Erythema marginatum. Arch Dis Child. 1955;30(152):359–65. 47. Perry CB.  Erythema marginatum (rheumaticum). Arch Dis Child. 1937;12(70):233–8. 48. Baldwin JS, Kerr JM, Kuttner AG, Doyle EF. Observations on rheumatic nodules over a 30-year period. J Pediatr. 1960;56:465–70. 49. Demirkesen C, Tuzuner N, Mat C, Senocak M, Buyukbabani N, Tuzun Y, Yazici H. Clinicopathologic evaluation of nodular cutaneous lesions of Behcet syndrome. Am J Clin Pathol. 2001;116(3):341–6. https://doi.org/10.1309/gcth-0060-55k8-xctt.

T. Habibullah et al. 50. Diri E, Mat C, Hamuryudan V, Yurdakul S, Hizli N, Yazici H. Papulopustular skin lesions are seen more frequently in patients with Behcet's syndrome who have arthritis: a controlled and masked study. Ann Rheum Dis. 2001;60(11):1074–6. 51. Tunc R, Keyman E, Melikoglu M, Fresko I, Yazici H. Target organ associations in Turkish patients with Behcet's disease: a cross sectional study by exploratory factor analysis. J Rheumatol. 2002;29(11):2393–6. 52. Hatemi G, Bahar H, Uysal S, Mat C, Gogus F, Masatlioglu S, et  al. The pustular skin lesions in Behcet's syndrome are not sterile. Ann Rheum Dis. 2004;63(11):1450–2. https://doi.org/10.1136/ ard.2003.017467. 53. Kim HA, Choi KW, Song YW. Arthropathy in Behcet's disease. Scand J Rheumatol. 1997;26(2):125–9. 54. Farhi D, Cosnes J, Zizi N, Chosidow O, Seksik P, Beaugerie L, et  al. Significance of erythema nodosum and pyoderma gangrenosum in inflammatory bowel diseases: a cohort study of 2402 patients. Medicine (Baltimore). 2008;87(5):281–93. https:// doi.org/10.1097/MD.0b013e318187cc9c. 55. Powell FC, Schroeter AL, Su WP, Perry HO. Pyoderma gangrenosum: a review of 86 patients. Q J Med. 1985;55(217):173–86. 56. Keltz M, Lebwohl M, Bishop S. Peristomal pyoderma gangrenosum. J Am Acad Dermatol. 1992;27(2 Pt 2):360–4. 57. Wordsworth P. Arthritis and inflammatory bowel disease. Curr Rheumatol Rep. 2000;2(2):87–8. 58. Halevy S, Ghislain PD, Mockenhaupt M, Fagot JP, Bouwes Bavinck JN, Sidoroff A, et  al. Allopurinol is the most common cause of Stevens-Johnson syndrome and toxic epidermal necrolysis in Europe and Israel. J Am Acad Dermatol. 2008;58(1):25–32. https://doi.org/10.1016/j.jaad.2007.08.036. 59. Sterry W, Steinhoff M. Papilosquamous and eczematous dermatoses. In: Bolognia JL, Jorizzo JL, Schaffer JV, editors. Dermatology. 3rd ed. 60. French IE, Prins C.  Urticaria, erythema and purpuras. In: Bolognia JL, Jorizzo JL, Schaffer JV, editors. Dermatology. 3rd ed.

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Cardiovascular Diseases and Rheumatology

16

Rania Alhaj Ali, Hussein Halabi, and Hani Almoallim

16.1 Introduction The prevalence of various cardiovascular diseases (CVD) in the different rheumatologic disorders is a very important topic. Each disease has a number of unique manifestations despite the fact that an overlap is present due to shared common risk factors, which may be related to the longer life expectancy of the recent therapeutic advances. A growing understanding of the role of inflammation and immune system in the initiation and progression of atherosclerosis as well as the early detection of cardiovascular manifestations is due to the availability and use of sophisticated noninvasive cardiac and vascular diagnostic technology. Such discipline results in the detection of cardiac manifestation unique to each rheumatologic disorder. This was not possible previously due to short life expectancy, limited therapeutic interventions, vague understanding

R. A. Ali (*) King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia e-mail: [email protected] H. Halabi Department of Internal Medicine, King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia H. Almoallim Medical College, Umm Al-Qura University (UQU), Makkah, Saudi Arabia © The Author(s) 2021 H. Almoallim, M. Cheikh (eds.), Skills in Rheumatology, https://doi.org/10.1007/978-981-15-8323-0_16

of pathological process for each disease, and the limited diagnostic resources. Cardiovascular diseases (CVD), including coronary artery diseases (CAD), can be present at the time of or after the diagnosis of rheumatologic disease. Cardiovascular association can be the principal introduction of the rheumatologic diseases in case of late diagnosis. The manifestations of CVD in rheumatologic diseases vary from subclinical to severe manifestations [4, 5], and they involve different structures of the heart. They can lead to significant morbidity and mortality. Therefore, we need to draw attention to their symptoms, to the risk factors that contribute to CVD development, as well as adaption of preventive measures that may control them. We will also consider the coronary artery disease (CAD), which maybe a crucial contributor to morbidity and mortality in numerous rheumatological diseases [6–9]. The prevalence of atherosclerotic CAD is increased in patients with chronic inflammatory rheumatic diseases, particularly in those with systemic lupus erythematous (SLE) and rheumatoid arthritis (RA) [10, 11]. The increased risk of CAD results from both traditional risk factors and factors unique to these rheumatic diseases [12, 13]. For example, accelerated atherosclerosis is one of the important risk factors for the development of CAD, and it can be attributed to the prolonged inflammatory process in these diseases, vascular endothelial dysfunction, and a specific form of 353

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low-density lipoprotein (LDL). The importance of metabolic syndrome in various rheumatic diseases and its implications on morbidity and mortality will be discussed as metabolic syndrome, which is commonly diagnosed among those patients and also plays an important role in the CVD development [14–16]. Several medications are now used in the management of various rheumatologic diseases, which can affect the development of CAD— either by decreasing or increasing the CAD severity or by decreasing or increasing its risk factors. In fact, many discussions are held nowadays with focus on how and when to use them. For example, the use of aspirin and statins in rheumatology and their effect on CAD. We will discuss the latest guidelines for their use here. In this chapter, we address the various cardiovascular events that patients are exposed to, with CAD as one of the major factors that increase their mortality [10]. We will also discuss the

important areas in regard to the identification of high-risk groups that need interventions, how to decrease the risk of CAD in these groups, and the way to better understand the effects of common medications on the risk of CAD in these patients.

16.2 Cardiovascular Manifestations in the Rheumatic Diseases In this section, we look at CVD involvements in the different rheumatologic diseases and address the important issues in regard to their development (Tables 16.1 and 16.2 give a summary of the points given below). The coronary artery disease (CAD) contributes significantly to the morbidity and mortality in various rheumatic diseases, whereas the occurrence of atherosclerotic CAD is increased in patients with chronic inflammatory rheumatic

Table 16.1  Type of CVD diseases Disease RA

CVD Atherosclerotic

Non-atherosclerotic

SLE

Pericardium Myocardium Endocardium and valves

Systemic sclerosis

Histology of CVD in SSc Myocardium

Pulmonary arteries

 • Myocardial infarction.  • Congestive heart failure.  • Peripheral arterial disease.  • Pericarditis. It is possible to occur as an inflammatory manifestation of RA.  • Myocarditis and endocarditis. They are also possible to occur as a complication in RA.  • Vasculitis. (e.g., aortitis, coronary arteritis) It can cause neurovascular disease (e.g., mononeuritis multiplex), cutaneous ulceration, or organ infarction based on the affected artery.  • Other less common complications. Conduction abnormalities  • Amyloidosis.  • Pulmonary hypertension.  • Pericarditis.  • Pericardial effusion.  • ECG findings: Prolonged PR intervals.  • MRI to help in diagnosis.  • Systolic murmur: Possibly from hyperdynamic state because of anemia.  • Libman-sacks endocarditis .  • Hemosiderin deposits.  • Involvement of subendocardial layers.  • Fibrosis affects the myocardium in both ventricles and the conducting system.  • Tricuspid regurgitation.  • Pulmonary hypertension with irreversible fibrosis at the arterial walls, which will cause resistance against right ventricular contraction.

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Table 16.1 (continued) Disease Antiphos­ ‑pholipid syndrome

CVD CAD Valvular disease Pseudo-endocarditis

Peripheral artery disease DVT

Ankylosing spondylitis

Intracardiac thrombus Conduction defects

Aortic incompetence Left ventricular dysfunction Less common

 • MI and cardiac death with APL positive.  • Unstable angina.  • Mitral, aortic, and less common in tricuspid valves.  • It can progress to heart failure.  • Vegetation commonly at the mitral and aortic valves.  • High APL.  • Blood culture is negative for infection.  • At lower extremities.  • Most common venous manifestation.  • Pulmonary embolism is a common eventual complication.  • Not common and usually misdiagnosed. Inflammation and fibrosis of interventricular septum will cause damage of atrioventricular node, which can lead to first, second, and third-degree heart block and bundle branch block Aortic wall inflammation (aortitis) above and behind sinuses of valsalva, and may extend below to the aortic roots and the wall of the mitral valve A possible increased connective tissue involvement in the myocardium  • Pericarditis.  • Cardiomyopathy.  • Mitral valve disease.  • Endocarditis .

 • CAD  • Cerebral vascular disease.  • Peripheral vascular disease. Inflammatory  • Myocarditis. myopathies  • CAD.  • Affected myocardial small vessels . Systemic  • CAD vasculitis  • Myocardium, pericardium, endocardium, and conduction system involvements.  • Peripheral vascular disease. Psoriatic arthritis

Table 16.2  Summarized types of CVD in rheumatologic diseases Disease MI CHF PAD PH Myocardial diseases Endocardial diseases Valvular disease Pericarditis Arteritis (coronary, aorta) Conduction defects

RA ✓ ✓ ✓ ✓ ✓ ± ✓ ±

SLE APS SSc ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓

AS PsA ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓







Symbol definitions, MI: Myocardial infarction, CHF: Congestive heart failure, PAD: Peripheral arterial disease, PH: Pulmonary hypertension, SSc: Systemic sclerosis, AS: Ankylosing spondylitis, PsA: Psoriatic arthritis. ±: in case of rheumatoid nodule

diseases, particularly those with SLE and RA. This again is emphasizing the importance of those conditions to the development of CAD. This increased risk is mediated by the presence of both traditional risk factors and factors unique to those with systemic inflammatory disorders. It is a matter of higher risk as well as the presentation. A larger proportion of patients with RA has a clinical silent CAD in comparison to demographically similar individuals in the general population. Patients with RA are also less likely to report chest pain during an acute coronary event than those without RA.  It is still uncertain why this is happening, but acceptable explanations include the following: many patients with active disease and joint damage are less physically active; therefore, they are less likely to place suf-

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ficient demand on the heart to elicit angina, which may attribute to RA pain. Patients with CAD tend to use nonsteroidal anti-inflammatory drugs (NSAID), glucocorticoids, or disease-modifying antirheumatic drugs (DMARDs), which can change their pain perception. Patients with rheumatoid arthritis (RA) have a reduced life expectancy when compared with the general population. Cardiovascular death is considered the leading cause of mortality in patients with RA; it is responsible for approximately half the deaths observed in RA [8]. Epidemiologic studies have shown that this increased mortality is largely attributed to cardiovascular diseases, primarily CAD.  Considerable evidence suggests that inflammation plays a role in the pathogenesis of atherosclerosis [10]. The prevalence of cardiovascular comorbidity is difficult to assess accurately since CAD has a tendency to remain silent in the rheumatoid patients, but deaths from CVD occur earlier than in the general population. It has also been suggested that the increased risk of CAD in RA precedes the onset of clinical rheumatoid disease [17]. The lowering of CAD morbidity and mortality by recognizing patients at risk, and revealing their nontraditional1 risk factors as well as their contribution in developing cardiovascular ­ complications are important. Many rheumatic ­ diseases have their share of these complications, e.g., RA, SLE, and vasculitis. The studies showed the importance of prevention strategies. Furthermore, many studies have been discussing various reasons of the increased in cardiac manifestations and the risk of mortality due to CAD.  One could be the increase of traditional risk factors and its explanation. The second could be the special nontraditional risk factors, which are related to the pathophysiology of rheumatic diseases (See Tables 16.1 and 16.2). Traditional risk factors include smoking,2 hypertension, diabetes mellitus (DM), hyperlipidemia, and obesity [12].

The nontraditional risk factors are associated with elevation of CAD occurrences, which include severity of the disease, more extra-­ articular manifestation at presentation, corticosteroids, NSAIDs, and the low socioeconomic status. The presence of the accelerated atherosclerosis in those patients is associated with CAD development and subsequently the increased mortality from CAD in them (Tables  16.3 and 16.4).

Patients are exposed to both the traditional risk factors of CAD and the nontraditional risk factors related to their disease. 2  Apart from the known effects of smoking on CAD, it

increases the severity of the rheumatoid arthritis, which can lead to atypical manifestation of the CAD and increasing the difficulty of the early detection (Tables 16.3 and 16.4).

1 

16.2.1 Rheumatoid Arthritis (RA) Rheumatoid arthritis is a chronic systemic inflammatory disease, which affects approximately 1% of the adult general population [18]. It has many extra-articular manifestations (e.g., heart and lung) in about 40% of patients with RA over their life time [19]. The mortality gap in comparison to the general population widened with the dramatic improvement in the overall mortality rate in the latter group [20]. For example, if we compare the general population to the patients with RA, there is an increased incidence of cardiovascular events, including myocardial infarction, stroke, and cardiac death among the patients with RA. Cardiovascular disease is recognized as the leading cause of death in RA patients, accounting for nearly 40% of mortality [18]. Patients with RA are at twofold increased risk for myocardial infarction and stroke, with risk increasing to nearly threefold in patients who have had the disease for 10 years or more [18]. Congestive heart failure appears to be a greater contributor to excess mortality than ischemia. This increased cardiovascular disease risk in RA patients seems to be independent of traditional cardiovascular risk factors. Pathogenic mechanisms include pro-­ oxidative dyslipidemia, insulin resistance, prothrombotic state, hyperhomocysteinemia, and immune mechanisms, such as T-cell activation

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Table 16.3  Prevalence of traditional risk factors Prevalence RA SLE General population

Smoking ↑↑ ↑ ↑

Hypertension ↑ ↑↑ ↑

Table 16.4  Effects of traditional risk factors on RA Effects of Smoking

Hypertension

DM

Dyslipidemia

BMI

RA ↑RA development ↑ RF and ACPA-positive RA ↑worse prognosis ↑more than the general population, it is unclear whether it is from under diagnosis or from under treatment ↑BP from NSAIDs, chronic corticosteroids, leflunomide, and cyclosporine Possible association between RA and insulin resistance Can predict a new cardiovascular event ↓ or ↑ Total lipid ↓ or ↑ LDL ↓↓HDL Can predate the diagnosis of RA ↑BMI and obesity = ↑other traditional risk factors = ↑worse prognosis = CVD ↓BMI and cachexia = acute inflammation

that subsequently lead to endothelial dysfunction, a decrease in endothelial progenitor cells, and arterial stiffness, which are the constitutes of accelerated atherosclerosis observed in RA patients [18]. These patients are greatly susceptible to CAD (myocardial infarction and angina), heart failure, pericarditis, myocarditis, atrial fibrillation, valvular heart disease, and cardiac amyloidosis.

16.2.1.1 Pericarditis Pericarditis is the most common cardiac manifestation in RA, which is usually an asymptomatic disease. Clinical pericarditis is observed in around 4% of the patients [21], which is lower than the autopsy proven one that occurs in around 30%–50% of patients with RA [22]. Patients with

DM ↑↑ ↑ ↑

Dyslipidemia ↑↑ ↑ –

Obesity ↑ ↑ ↑

RA are more likely to develop pericardial effusion than the ones without RA by ten times [23]. Most of the patients develop the pericardial effusion after the onset of the arthritis; however, RA was diagnosed after pericardial effusion in a minority of patients [3]. The variables associated with the development of extra-articular manifestations including pericarditis are as follows: male gender, presence of increased serum concentrations of rheumatoid factor, joint erosions, subcutaneous nodules, number of disease-modifying antirheumatic drugs (DMARD), presence of nail fold lesions, and any other extra-articular feature 1 year before the time of the diagnosis, or treatment with corticosteroids at the time of the diagnosis [21]. Patients with findings of edema, shortness of breath, chest pain, raised jugular venous pressure, pericardial rub, and paradoxical pulse were found to have 100% mortality rate within 2 years [4]. In patients with pericardial effusion, the diagnosis of RA was mainly clinical without the need for invasive procedure [3]. Biologic agents are now considered one of the cornerstones of RA therapy associated with the development of pericardial effusion mostly within 4 months of the start of the infliximab and etanercept [24]. Purulent pericardial effusion was reported in patients receiving infliximab and etanercept [25, 26]. Treatment: Although most of the evidence came from patients with immune-mediated pericarditis, it can be extrapolated to the RA-associated pericarditis as follows: 1. Asymptomatic disease usually diagnosed accidently will resolve spontaneously. 2. Symptomatic disease therapy includes the following: • Nonsteroidal anti-inflammatory drug (NSAID) is the mainstay therapy for idio-

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pathic pericarditis, and the two agents that proved their efficacy are ibuprofen and indomethacin [27]. –– Corticosteroids: low- to moderate-dosage prednisone (0.2–0.5  mg/kg per day) for 4  weeks and then slowly tapered, if the patient is intolerant to aspirin or NDSAID or with pericardial effusion [27]. –– Colchicine: in patients with acute and recurrent pericarditis in addition to aspirin or NSAID in the dose of 0.5 mg twice daily in patients >70 kg and 0.5 mg once daily in patients ≤70 kg [27]. –– If previous medical treatment fails, there is growing evidence for oral azathioprine, intravenous human immunoglobulins, and anakinra [27]. –– Tocilizumab was reported to be successful too [28, 29]. –– Surgical management includes pericardiocentesis, pericardiectomy, or pericardiotomy in the cases of hemodynamic compromise, cardiac tamponade, or constrictive pericarditis. –– Biologic-agents-associated pericarditis should be stopped and treated accordingly [24]. –– Purulent pericarditis with biologic agents should be stopped and antibiotic therapy to be used accordingly [25, 26].

16.2.1.2 Myocardial Involvement Myocarditis is less common than RA-associated pericarditis. It was found in 19% of patients with RA based on post-mortem study where the majority were females with active arthritis; however, most of the patients with myocarditis were clinically asymptomatic [30]. Cardiomyopathy with finding of left ventricle hypertrophy (LVH) was found in around 37% of asymptomatic RA patients by echocardiography [31]. The pathohistological finding was either diffuse or focal inflammation of the myocardium [32]. Diagnosis: The left ventricle function is usually evaluated with echocardiography, but it has a limited role in the evaluation of myocardium involvement. Cardiac magnetic resonance imag-

ing (CMR) is helpful as noninvasive evaluation tool for myocarditis as it shows increased T2-weighted edema ratio (ER) score suggesting myocardial tissue edema. It has a role too in identifying the chronicity of myocarditis [33]. Treatment: Conventional therapy to support the left ventricle function is generally used. High-­ dose prednisolone (60  mg) daily for 2  months, tapered over 4 months followed by maintenance dose, normalizes the left ventricle ejection fraction and the gallium uptake [34]. Antimalarials-Induced Cardiotoxicity Hydroxychloroquine and chloroquine are medications initially used as antimalarial treatment. They found to be effective as disease-modifying antirheumatic drugs. Hydroxychloroquine-­ induced cardiotoxicity has been reported in patients with RA [35]. Risk factors: Old age, female sex, long duration of therapy, high daily dose, preexisting cardiac disease, or renal impairment [35]. Presentation: Features of systolic dysfunction and prolonged QT interval were reported too [35]. Diagnosis: (a) Echocardiography shows diffuse thickening ventricular walls [35]. (b) CMR: Shows areas of patchy gadolinium enhancement. It is important to differentiate it from other causes of cardiomyopathy [35]. (c) Endomyocardial biopsy: Shows enlarged and vacuolated cells, and the presence of myeloid and curvilinear bodies within the cardiac myocytes [35]. Treatment: Mainly withdrawal of the antimalarial agents and conventional heart failure treatment if needed [35].

16.2.1.3 Heart Failure It is a clinical syndrome that is two times higher in RA patients than the general population [36]. Associations: Rheumatoid factor positivity was associated with higher risk of congestive heart failure [36]. Causes: Patients with RA develop heart failure mostly due to ischemic cardiomyopathy,

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drug-induced myopathy (e.g., antimalarial drugs), rheumatoid nodule, NSAID use, or amyloidosis. Treatment: Treat the underlying cause and conventional heart failure treatment. Avoid the use of tumor necrosis factor-alpha (TNF alpha) inhibitors especially the high doses (10 mg/kg) in NYHA classes 3 and 4 heart failure [37]. In patients with congestive heart failure and RA, the combined use of synthetic DMARDs, non-TNF biologic, or tofacitinib over TNF inhibitors is recommended [38].

risk factors and effective disease control through immunosuppression [39]. The more extended the span of the RA and the utilization of TNF alpha inhibitors are, there is a chance for improvement of atherosclerosis [40]. The two are a surrogate for the seriousness of the illness and a presence of coronary calcification [41]. Male gender and severe inflammatory state (high inflammatory markers and disease activity score) are usually associated with atherosclerosis [42]. Factors influencing cardiovascular disease in rheumatoid arthritis:

16.2.1.4 C  oronary Artery Disease (CAD) Patients with rheumatoid arthritis (RA) have a reduced life expectancy when compared with the general population, where cardiovascular death is considered the leading cause of mortality in patients with RA; it is responsible for approximately half the deaths observed in RA [8]. Epidemiologic studies have shown that this increased mortality is largely attributable to cardiovascular diseases, primarily CAD. Considerable evidence suggests that inflammation plays a role in the pathogenesis of atherosclerosis [10]. The prevalence of cardiovascular comorbidity is difficult to assess accurately because CAD has a tendency to remain silent in the rheumatoid patient, but deaths from CVD occur earlier than in the general population. It has also been suggested that the increased risk of CAD in RA precedes the onset of clinical rheumatoid disease [17]. Traditional risk factors for atherosclerosis, such as smoking, hypercholesterolemia, hypertension, DM, and sedentary lifestyle, may be more common in RA than in the population as a whole but do not account for all of the increase in the disease. Currently, there is a large body of evidence that a chronic inflammatory state can enhance the harmful effects of some traditional risk factors, such as the association between systemic inflammation and arterial wall stiffness in hypertension or the proatherogenic lipid profile (high LDL and lipoprotein (a) low HDL) seen with increasing rheumatoid disease activity. The burden of addressing CAD in RA is therefore divided between rigorous control of traditional

• Oxidized LDL (oxLDL) and antibodies to oxidized LDL are both established as significant risk factors for CVD in RA. It has been consistently observed that the levels of oxLDL are higher in patients with active disease [39]. • C-reactive protein: Higher levels of CRP are associated with CVD in non-RA patients [39]. Treatment of CAD with statins or angiotensin-­ converting enzyme (ACE) inhibitors has been demonstrated to lower CRP levels [39]. Attention was specifically focused on high-­ sensitivity CRP (hsCRP). Raised hsCRP is found in hypertension, smoking, and DM, as well as CAD. In RA baseline, CRP predicts cardiovascular mortality [43], and the molecule acts directly in a pro-inflammatory manner at a range of sites. For example, CRP activates vascular endothelial cells to express adhesion molecules in a dose-dependent manner, and CRP activates monocyte chemotactic protein-1 (MCP-1), which can be inhibited by statins and fenofibrates [39]. • Homocysteine: Homocysteine is increasingly regarded as an epiphenomenon of CAD rather than a causative factor [39]. Elevated levels of homocysteine have been associated with CAD in the general population as well as in reduced levels of various vitamins including folate and B6 [39]. It has also been shown that homocysteine is present in higher concentrations in the joints of RA patients, where it may enhance production of pro-inflammatory cytokines such as IL-1 and thus act as a driver for

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joint damage; it may also accelerate atherosclerosis in a similar manner [44]. • • Physical disability due to rheumatoid arthritis: Poor functional status, especially in the lower limbs, is a powerful predictor of mortality in RA, while regular exercise is known to have beneficial effects on the cardiovascular system. Exercise capacity is also inversely related to the presence of metabolic syndrome [45]. Patients with chronic RA have physical disabilities, which prevent them from taking regular exercise. This influences CAD in several ways; the presence of CAD usually causes delay in the individual’s presentation to clinician since reduced physical activity may not exacerbate symptoms. The delay in presentation would also prevent treatment at an earlier stage of CAD, even with the lack of CVD, physical disability would still stop adequate exercise. • Leptin and the adipocytokines: Leptin is an adipokine that functions both as a hormone and a cytokine. It is produced by the adipose tissue, and its main role appears to be to reduce food intake and to stimulate the sympathetic nervous system. It is known to stimulate inflammatory cytokine production, and to have direct deleterious effects on articular cartilage. It is also known to cause endothelial dysfunction, oxidative stress, and platelet aggregation and to be elevated in RA; while fasting has been implicated as a means of reducing leptin levels and improving RA disease activity [39]. Leptin has the potential to play a key role linking obesity, inflammation, and cardiovascular damage. Prevention of CAD in RA. Since it is generally similar to prevention in patients without RA [46], here are some important points to prevent CAD in RA patients. One needs to: • Stop smoking. • Measure fasting blood glucose annually or in the event of significant weight gain especially in patients taking steroids. In already diabetic

• • •



patients, the steroids should be kept in the lowest dose. Monitor blood pressure for RA patients before beginning medications and then at regular intervals for patients using NSAID, cyclosporine, and corticosteroids. NSAIDs reduce the antihypertensive effects of diuretics, β-blockers, and angiotensin-converting enzyme inhibitors, but it is less likely to interfere with calcium channel blockers [47]. In those group of patients either to increase the dose of the antihypertensive medications or to use a calcium channel blocker. Manage hypercholesterolaemia according to recommendation for the general population. Manage obesity as well as weight loss. Supplement the diet with fish oil that is rich in omega-3 fats, because this has demonstrated efficacy in the treatment of RA, facilitated reduction of NSAIDs use and reduced cardiovascular mortality risk [48]. Diagnose and treat RA early: –– Methotrexate: shown to decrease cardiovascular mortality among RA patients [49]. –– TNF inhibitors: shown to decrease the risk of MI among patients who have controlled synovitis within 6 months of treatment [50].

16.2.1.5 Rheumatoid Nodule Valvular nodule is 10 times higher in RA patients than the general population [23]. Incidence: Echocardiographic evidence of aortic valve nodule was observed less than mitral valve nodule in the rate 0.3% vs. 0.6% among RA patients [31], respectively. Presentation: Differs according to the site of the nodule, as it causes functional impairment, such as arrhythmias and valve disease [51]. It was associated with complete atrioventricular (AV) block necessitating pacemaker as it involves the AV node [52, 53]. Treatment: According to the presentation.

16.2.2 SLE It is a multisystem autoimmune disease with a strong female predilection.

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Cardiovascular morbidity and mortality is a frequent complication, particularly in females aged 35–44 years, where the risk of myocardial infarction is raised 50-fold [54]. The cardiac morbidity is the most common cause of death in SLE patients, which is around 25% of deaths in SLE [55]. The heart is one of the most frequently affected organs in systemic lupus erythematosus (SLE), where any part can be affected, including the pericardium, myocardium, coronary arteries, valves, and the conduction system. In addition to pericarditis and myocarditis, high incidence of CAD has become increasingly recognized as cause of mortality, especially in older adult patients and those with long-standing SLE [56]. Pericarditis is the most common cardiac abnormality in SLE patients, but lesions of the valves, as well as myocardium and coronary vessels, may all occur. In the past, cardiac manifestations were severe and life threatening, often leading to death. Therefore, they were frequently found in postmortem examinations. Nowadays, cardiac manifestations are often mild and asymptomatic. However, they can be frequently recognized by echocardiography and other noninvasive tests (Echocardiography is a sensitive and specific technique in detecting cardiac abnormalities, particularly mild pericarditis, valvular lesions, and myocardial dysfunction). Therefore, echocardiography should be performed periodically on SLE patients [57].

16.2.2.1 Pericarditis The most common clinical cardiovascular manifestation of SLE. Prevalence: Echocardiographic evidence of pericardial effusion was detected in 27% of SLE patients, where most of them had asymptomatic disease [58]. Lupus pericarditis occurs predominantly in females in around 92% [59] which is mostly due to main predominance of SLE in females. Associations: Mostly associated with active SLE in 93% and involvement of other organs with SLE in 72% [59]. In the absence of renal failure, constrictive pericarditis or pericardial effusion is rarely reported [60]. Patients with tamponade had lower serum level of C4 in com-

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parison to the ones who did not develop tamponade [61]. Clinical presentation: Ranges from asymptomatic to pericardial effusion [58] to cardiac tamponade in 16% [59]. Diagnosis: Either by the presence of pericardial effusion by echocardiography only or the presence of 2 out of 4 of the following (Retrosternal pain, pericardial friction rub, widespread ST-segment elevation, and new/ ­ worsening pericardial effusion) among SLE patients [59]. Treatment: The treatment of lupus pericarditis is mainly derived from immune-mediated pericarditis, as previously mentioned in the RA section, where it responded well to NSAID and corticosteroids [59]. High-dose corticosteroids, complete drainage, and pericardial window were used for treating patients with large pericardial effusion/tamponade [61, 62].

16.2.2.2 Myocarditis Effects: SLE is associated with the increase in the left ventricle mass, and this would be even more if SLE was associated with hypertension (HTN) [63]. Associations: The association is strong between lupus myocarditis with the presence of myositis but weak with the presence of the antibodies to nuclear ribonucleoprotein (RNP) [64]. High SLE Disease Activity Index is an independent risk factor in the development of lupus myocarditis [5], where anticardiolipin IgG and lupus anticoagulant were positive in patients with severe symptoms [65]. Clinical features: It ranges from asymptomatic disease discovered accidently to symptomatic heart failure and sudden death [5]. Diagnosis: Echocardiography: Most patients suffered from wall motion abnormalities (WMA), whereas less than 50% of lupus myocarditis patients showed decrease in the left ventricle ejection fraction after the exclusion of other causes of myocarditis [5]. Treatment: Conventional treatment of heart failure [5]. Immunosuppressive therapy (high-­ dose systemic corticosteroids with subsequent dose tapering, intravenous immunoglobulin, plasmapheresis, or cyclophosphamide) showed

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improvement in heart failure symptoms, EF, and the WMA of the heart [5]. After corticosteroids therapy, the EF improved up to a mean of 49.5% after around 7 months of follow-up from a mean of 33.8% [66]; one article reported normal EF after follow-up [67]. Refractory lupus myocarditis can be treated with rituximab [68]. Intravenous “pulse” cyclophosphamide was used in patient with lupus myocarditis refractory to corticosteroids, and it showed improvement in heart failure symptoms and EF from 19% to 63% [69]. Mycophenolate mofetil was effective in a case series [70]. Intravenous immunoglobulin was effective in the treatment of patients with severe lupus myocarditis in conjunction with corticosteroids and cyclophosphamide [65]. One rare case report showed that plasmapheresis and extracorporeal membrane oxygenation (ECMO) were effective in lupus myocarditis [71].

16.2.2.3 C  oronary Artery Disease (CAD) Prevalence: The prevalence of the angina, myocardial infarction, and sudden cardiac death was found to be 8.3% as per a Johns Hopkins SLE cohort study [9]. Another study found more than 50-fold risks of MI in young women 35–44 years old when compared to the control group [11]. Risk Factors (a) Traditional risk factors for atherosclerosis. It has an increased prevalence in patients with SLE as hypertension, DM, premature menopause, sedentary lifestyle, and high homocysteine level [12]. (b) Inflammation-related risk factors. • High disease activity and elevated level of CRP [13]. • In lupus nephritis, it was found that patients with long-term lupus nephritis had frequent episodes of cardiac lesions, mainly cardiac infarctions [72]. • Low serum levels of C3, antiphospholipid antibodies (APL), and elevated levels of antibodies to anti-ds DNA were found to be independent predictors of thrombosis. Hydroxychloroquine is pro-

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• • • •

tective against future thrombosis in those patients [73]. Several autoantibodies such as anti-DNA, APL, anti-SSA (Ro antibodies), and anti-­ endothelial cell antibodies present in patients with SLE can mediate cardiac damage [74]. Old age at diagnosis of SLE [9, 11]. Longer duration of SLE [9, 11]. Longer duration of steroid therapy [9]. High levels of oxidized low-density lipoprotein cholesterol and homocysteine [9].

Preventions of CAD in SLE. To prevent CAD, one has to: • Control the traditional risk factors, to use the statins according to the guidelines for the general population, and to control blood pressure aggressively. • Improve the lipid profile by using hydroxychloroquine as it lowers the level of the cholesterol in the blood, especially in patients taking steroids [75], and it is associated with a reduced risk of DM [76]. • Minimize the use of steroids.

16.2.2.4 Endocarditis (Libman–Sacks Endocarditis) It was first described by Libman and Sacks in 1942 after they discovered valvular lesions in four patients with SLE. Prevalence: Echocardiographic evidence was detected in around 11% of patients with SLE [77]. Associations: It was found to be associated with longer SLE duration and activity, thrombosis, stroke, thrombocytopenia, and antiphospholipid syndrome [77]. Its coexistence with antiphospholipid antibodies (APLs) increases the risk of thromboembolic complications, especially stroke [78]. Pathology: Since the main involved valve is the mitral followed by the aortic [78], the left side is mainly more involved than the right. Therefore, the main dysfunction is regurgitation; stenosis is rarely found [78]. Diagnosis: Echocardiography: It is manifested as valve vegetations, thickening, and/or

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regurgitation [79]. Transesophageal echocardiography (TEE) was found to be more sensitive than transthoracic echocardiography (TTE) for the detection of echocardiographic findings [79]; for example, valvular thickening was found higher with TEE at 70% vs. 52% with TTE [79]. How to differentiate it from infective endocarditis? Infective endocarditis is an uncommon complication of SLE, yet at the same time, it should be in the differential diagnosis as both diseases can be presented with fever and valvular vegetation. Three laboratory tests can help differentiate between them to a degree, and these are the white blood cell count (WBC), the CRP level, and the antiphospholipid antibody (APL) level [80]. The test results show that the WBC is expected to be low during lupus flare and high during infection, CRP is high with infection and suppressed during lupus flare, and the aPL is high in SLE and unlikely to be positive in infection [80]. Treatment The control of the SLE disease activity is important with the use of the corticosteroids. Although the use of corticosteroid is not beneficial for the valve lesion, it is important to control underlying diseases [78]. The corticosteroids, on the other hand, were noted to be associated with fibrosis and severe dysfunction (e.g., mitral valve insufficiency) after high doses of corticosteroid are used [81, 82]. Patients with Libman–Sacks Endocarditis, who suffered from a thromboembolic event, are recommended to be on life-long anticoagulation to prevent further episodes [78]. Accordingly, conventional treatment of heart failure and valvular lesion as needed is crucial.

16.2.3 Systemic Sclerosis (SSc) Widespread vascular lesions, fibrosis of the skin, and internal organs characterize a connective tissue disease. More than half of the patients with SSc, who underwent autopsy, were found to have significant cardiac abnormalities [37]. Cardiac involvement is recognized as a poor prognostic factor when clinically evident, with a 5-year mortality rate is around 75% [83]. Primary myocardial involvement is common in SSc; increasingly,

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evidence strongly suggests that myocardial involvement is related to repeated focal ischemia leading to myocardial fibrosis with irreversible lesions. Reproducible data have shown that this relates to microcirculation impairment with abnormal vasoreactivity, with or without associated structural vascular abnormalities. Consistently, atherosclerosis and macrovascular coronary lesions do not seem to be increased in SSc. Myocardial involvement leads to abnormal systolic, diastolic left ventricular dysfunction, and right ventricular dysfunction. Sensitive and quantitative methods have demonstrated the ability of vasodilators—including calcium channel blockers and angiotensin-converting enzyme inhibitors—to improve both perfusion and function abnormalities. By that, they emphasize the critical role of microcirculation impairment [84]. Asymmetric hypertrophy of the interventricular septum with signs of sub-aortic obstruction consistent with hypertrophic obstructive cardiomyopathy was evident in echocardiogram in patients with diffuse SSc. Hypertrophic cardiomyopathy is associated with the human lymphocyte antigen HLA DR3 [85], and this may provide a possible link with SSc as this HLA phenotype is common in the latter condition [85].

16.2.3.1 Myocardial Fibrosis Prevalence: Around 66% of patients with SSc based on MRI [86]. The presence of the left ventricle (LV) dysfunction (ejection fraction (EF) 50 Aspirin 75–162 mg daily

Aspirin 75–162 mg daily A dose >162 mg offersno additional benefit in preventing CVD

Fig. 16.2  The use of aspirin for primary and secondary prevention of CAD [161]

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375 Use of Statins

LDL-C >190 mg/dl

Clinical ASCVD age (40 to 75) Age > 75

High intensity statins

Age < 75

Estimated 10-y ASCVD risk ≥ 7.5% Moderate intensity stains

High intensity statins Diabetic

Non-diabetic

Diabetic

High intensity statins

Moderate intensity statins

Moderate intesity statins

High Intensity Statins Therapy • Atorvastatin 40–80 mg • Rosuvastatin 20–40 mg Moderate Intensity Statin Therapy • Atorvastatin 10–20 mg • Rosuvastatin 5–10 mg • Simvastatin 20–40 mg • Pravastatin 40–80 mg • Lovastatin 40 mg • Fluyastatin XL 80 mg • Fluyastatin 40 mg • Pitavastatin 2–4 mg

Fig. 16.3  The use of the statins for management of CAD [159]

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381 lar systolic dysfunction in rheumatoid disease: an unrecognized burden? J Am Coll Cardiol. 2006;47(6):1169–74. 156. Lee JL, Naguwa SM, Cheema GS, Gershwin ME. Revisiting Libman-sacks endocarditis: a historical review and update. Clin Rev Allergy Immunol. 2009;36(2–3):126–30. 157. Gramling A, O'Dell JR.  Initial management of rheumatoid arthritis. Rheum Dis Clin N Am. 2012;38(2):311–25. 158. Wei L, MacDonald TM, Walker BR. Taking glucocorticoids by prescription is associated with subsequent cardiovascular disease. Ann Intern Med. 2004;141(10):764–70. 159. Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, et  al. 2013 ACC/ AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association task force on practice guidelines. Circulation. 2014;129(25 Suppl 2):S1–45. 160. Rubin LJ, Badesch DB, Barst RJ, Galie N, Black CM, Keogh A, et  al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002;346(12):896–903. 161. Park K, Bavry AA.  Aspirin: its risks, benefits, and optimal use in preventing cardiovascular events. Cleve Clin J Med. 2013;80(5):318–26.

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Gestational Rheumatology

17

Hanan Al-Osaimi and Areej Althubiti

17.1 Introduction There are changes that occur in the maternal organ systems due to increased demands of pregnancy. Most of the rheumatic disorders occur in the reproductive age group. The hormonal changes that occur during pregnancy may mimic the signs and symptoms of rheumatic disorders thereby making the diagnosis difficult. Rheumatological disorders need to be diagnosed and treated at least 6 months before the onset of pregnancy; otherwise they may have considerable effect on the prognosis of the disease. This is particularly evident in cases of SLE and anti-­ phospholipid antibody syndrome. Therefore, pregnancy is a crucial issue that needs to be clearly addressed in details in all female patients in the reproductive age group having some of the rheumatological disorders. There are two concerns in these patients. The first one is the effect of the disease activity on pregnancy, and the second is the influence of pregnancy on the disease. That explains why pregnancy should be planned carefully at least 6  months of remission before attempting pregnancy. This is supported with close follow-up for the disease activity during pregnancy. Therefore, H. Al-Osaimi (*) King Fahad Armed Forces Hospital, Jeddah, Saudi Arabia A. Althubiti Saudi Commission for Health Specialties, Riyadh, Saudi Arabia © The Author(s) 2021 H. Almoallim, M. Cheikh (eds.), Skills in Rheumatology, https://doi.org/10.1007/978-981-15-8323-0_17

managing pregnant patients with rheumatic disease can be very challenging. The simple explanation is the combination of aggravation of disease by pregnancy, the aggravation of pregnancy by disease, and the use of special medications in pregnancy. A successful pregnancy requires achievement of multiple biological steps from “conception, embryogenesis, placental and fetal development, maternal-fetal communication to labor and delivery” [1].

17.2 Objectives By the end of this chapter, you should be able to: 1. To discuss the physiology of pregnancy. 2. To discuss systemic lupus erythematosus flare manifestations and management during pregnancy. 3. To diagnose and manage antiphospholipid syndrome during pregnancy. 4. To discuss neonatal lupus erythematosus pathophysiology and management. 5. Review management of other common rheumatologic diseases during pregnancy.

17.3 Physiology of Pregnancy There are added burden by the mother, the fetus, and the placenta during pregnancy. All of these should be met by the mother’s organ systems. 383

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Thus, there are certain cardiovascular, hematological, immunological, endocrinal, and metabolic changes that happen in the mother in normal pregnancy.

17.3.1 Changes in Cardiovascular System The most important physiological changes that happen in pregnancy are the increase in cardiac output and retention of sodium and water. These changes result in significant increase in blood volume and reduction in systemic vascular ­resistance and blood pressure. Such changes start as early as fourth week of pregnancy, reaching their highest level during the second trimester, and then remain relatively constant until delivery. As the increase in the red cell volume is proportionately much less than the increase in plasma volume, there is hemodilution (physiological anemia) by the end of second trimester [2]. The increased level of plasma erythropoietin is responsible for balanced increase in the red cell mass. The physiological anemia that happens in pregnancy reduces the cardiac work load and helps for enhanced placental perfusion by decreasing the blood viscosity. It also decreases the risk of thrombosis in uteroplacental circulation. The increased blood volume also defends against the usual blood loss in the peripartum period. Cardiac output increases by 30–50% during normal pregnancy. This is as a result of increase in the preload owing to rise in blood volume, decrease in afterload due to decrease in systemic vascular resistance, and increase in the maternal heart rate. The cardiac output and systemic vascular resistance steadily return to non-pregnant levels over a period of 3 months postpartum [3].

17.3.2 Hematological Changes The total white cell count is increased up to 40%, and the platelet count gradually declines till the term, while they do not fall below 100,000/cu mm. This is expected as a result of dilutional effect, increased destruction, and turnover [4].

H. Al-Osaimi and A. Althubiti

17.3.3 Changes in Coagulation System Pregnancy is linked with changes in several coagulation factors that result in a 20% reduction of prothrombin and the partial thromboplastin times creating a hypercoagulable state. This acts as a double-edged sword, both for protection (e.g., hemostasis contributing to reduced blood loss at delivery) and increased risk (e.g., thromboembolic phenomenon). Venous thrombosis in pregnancy happens in approximately 0.7 per 1000 women and is three- to fourfold higher in the puerperium than during pregnancy. The risk is amplified in women with underlying inherited thrombophilia (e.g., factor V Leiden or the prothrombin gene mutation) [5].

17.3.4 Changes in the Maternal Immune System The local modification of the maternal immune system is accountable for the successful coexistence between the mother and the fetus/placenta expressing both maternal (self) and paternal antigens. The cell-mediated adaptive immune responses are reduced, bypassed, or even eliminated. However, the antibody-mediated immunity is reformed, while the natural immunity (innate immunity) remains intact which continues to offer the host defense against infection. During insemination, the transforming growth factor β1 (TGF-β1), found in the seminal fluid, excites the production of granulocyte-­ macrophage colony-stimulating factor (GM-CSF) and enrolment of inflammatory cell infiltrates in the uterus [6]. During implantation of the fertilized ovum, the majority of the lymphocytes infiltrating the decidua are typical uterine natural killer (NK) cells which are CD56++, CD16-, and CD3- and express various receptors. Uterine decidua and the fetoplacental unit produce large number of cytokines which contribute to shift of the immune response from T helper 1 (Th1) to T helper 2 (Th2) response. While there are many specific mechanisms for immunological protection

17  Gestational Rheumatology

against the fetus, the most essential one is altered HLA expression [7].

17.3.5 Changes in the Endocrine Glands Maternal changes in pregnancy involve the hypothalamus, pituitary, parathyroid, adrenal glands, and ovaries to adapt the needs of the fetal-­ placental-­maternal unit. The hypothalamus still controls much of the endocrine system through hypothalamic-pituitary axis, directly affecting the function of the abovementioned endocrine organs. (a) Hypothalamus: These hormones released from hypothalamus are available in high concentrations in portal circulation where they are biologically active. The circulating concentrations of many of these hormones are also raised in pregnancy due to placental production of identical or variant hormones [8]. The most important changes are seen in the following hormones: Gonadotropin-releasing hormone (GnRH) level increases during pregnancy. The main source is the placenta and exerts a main role in placental growth and function. Corticotropin-releasing hormone (CRH) from hypothalamus is engaged in stress response in pregnancy and delivery. It is also released by the placenta, chorionic trophoblasts, amnion, and decidual cells. The placental CRH do not stimulate adrenocorticotropic hormone (ACTH) secretion but helps in induction of labor. Besides CRH the gestational tissues also secrete urocortin which shares the same function as that of placental CRH. The urocortin-2 also controls the tone of vascular endothelium which also plays a major role in parturition [9]. (b) Pituitary Gland: Anterior lobe of pituitary gland expands threefold during gestation because of hypertrophy and hyperplasia of lactotrophs. It needs minimum 6  months after delivery to return to normal size. Follicle-­stimulating hormone (FSH), lutein-

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izing hormone (LH), and thyroid-stimulating hormone (TSH) levels are decreased, while growth hormone (GH), ACTH, and prolactin (PRL) levels are increased mainly due to the synthesis by the placenta. The serum PRL concentration increases due to increase estradiol during pregnancy, reaching the maximum at delivery to prepare the breast for lactation. The plasma sodium concentration drops by 5 meq/L due to resetting of osmoreceptors as a result of increased levels of human chorionic gonadotropin (HCG). Oxytocin level increases steadily during gestation and is involved in parturition and lactation. There is increase in thyroxin-binding globulin (TBG) but TSH (along with triiodothyronine (T3) and thyroxin (T4)) is in the normal range [10]. The renin-angiotensin-aldosterone system is stimulated during pregnancy due to reduction in peripheral vascular resistance and blood pressure, but there is a gradual decline in vascular responsiveness to angiotensin II. The aldosterone level increases by four- to sixfold, and the blood pressure usually reduces by 10 mmHg. Relaxin, a vasodilator factor produced by the placenta and aldosterone, is critical in sustaining sodium balance in the setting of peripheral vasodilatation. During pregnancy there is an increase in the levels of maternal and placental ACTH, cortisol-­ binding protein, atrial natriuretic peptide (ANP), plasma rennin activity (PRA), sex hormone-­ binding protein, and testosterone levels [11].

17.4 Systemic Lupus Erythematosus 17.4.1 Introduction Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disease occurring in young women in their childbearing age. It is one of the most common rheumatological conditions encountered in pregnancy with considerable influence on its outcome. It mainly affects the skin, joints, blood, kidney, and other organs. Pregnancy can have influence on the disease, and

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the disease also has considerable influence on pregnancy. The annual incidence of SLE is 3 cases per 100,000 population out of which 90% belong to the female gender. Asians and African Americans found to have more severe disease with renal involvement. The thrombotic complications are seen in 10% of these cases [12]. SLE is a hypercoagulable state due to antiphospholipid antibodies and increase in certain procoagulants due to inflammation and platelet hyperfunction. This further leads to thrombogenesis by multiple-hit theory. The factors which increase thrombosis risk also encourage pregnancy loss in lupus.

17.4.2 Influence of Pregnancy on SLE SLE patients experience different kinds of pregnancy related complications more than non-SLE women. One of the common pregnancy-related complications are pregnancy-induced hypertension (PIH); preeclampsia (blood pressure ≥ 140/90 mmHg after 20 weeks of gestation and proteinuria ≥300 mg/24 hrs), eclampsia (preeclampsia plus seizures), HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets), and gestational diabetes [13].

17.4.3 Lupus Flares The risk of lupus flare is enlarged if the woman has had active lupus in the last 6 months of pregnancy. Therefore, quiescent disease at the onset of pregnancy offers optimum protection against the occurrence of flare during pregnancy [14]. Lupus may flare through any trimester of pregnancy or postpartum period. The flares are usually mild mainly involving the joints, skin, and blood. Some of the physiological changes of pregnancy can simulate the symptoms of the active disease such as palmar erythema, arthralgia, myalgia, and lower limb edema. The laboratory data specific for lupus flare as compared to pregnancy data include rising titer of anti-double strand DNA antibodies, presence of red blood cell casts in the urine, positive direct

H. Al-Osaimi and A. Althubiti

Coombs test, and presence of antiplatelet antibody with thrombocytopenia. Complement levels can be in natural range as complement levels increase during pregnancy due to estrogen-­ induced hepatic synthesis of complements. Hence, it is important to differentiate lupus flare from pregnancy-related complications and physiological changes of pregnancy [15]. Previous studies have suggested that several factors may increase the risk of preeclampsia in pregnancies complicated by SLE.  These factors include preexisting hypertension, renal insufficiency, presence of APS, as well as active SLE [16]. The differentiating features of preeclampsia from lupus nephritis are mentioned in Table 17.1.

17.4.4 Lupus Nephritis (LN) Lupus pregnancies with long-standing LN are at high risk of spontaneous abortions and increased perinatal and maternal mortality. However, the outcome of pregnancy in patients with stable LN at conception is relatively favorable. Remission in lupus nephritis has been defined as stable renal function, a serum creatinine within the normal range, urinary red cells below 5/high power field, proteinuria below 0.5  g/day, and ideally normal Table 17.1  Broad guidelines to differentiate lupus nephrites from preeclampsia Active lupus Parameter nephritis Preeclampsia High BP Present or absent Diastolic BP > 90 mmHg • >300 mg/24 h Proteinuria • >500 mg/24 h if normal if normal baseline baseline • Occur during • Doubling if third trimester. >500 mg/24 h at baseline. • Occur before third trimester. Edema Present/absent Present/absent Active Present/absent Absent sediment Uric acid Normal or elevated Elevated C3, C4 Low Normal Anti-ds Rising Absent DNA abs

17  Gestational Rheumatology

serum complement component 3 (C3) levels for the last 12–18 months [17]. LN flare can be associated with other findings of active lupus such as serositis, arthritis, and high titers of anti-DNA antibodies. The proteinuria of preeclampsia decreases after delivery but not that of active lupus patient.

17.4.5 Influence of SLE on Pregnancy SLE patients are as fertile as the overall female population [18]. Reduced fertility rate is seen in patients with active disease on high-dose steroids, patients with proven renal disease, and patients with moderate to severe renal failure. End-stage renal disease resulting from LN can lead to amenorrhea. However, amenorrhea in renal patients may also be because of ovarian failure from cyclophosphamide use or of autoimmune origin [19]. Lupus flares can occur at any time during pregnancy with potential adverse effects on the conception. Lupus flares happen more commonly throughout pregnancy and postpartum period more than in non-pregnant SLE patients. Increase in lupus activity is seen at least in 1/3 cases in pregnancy. Therefore, for a better outcome of lupus pregnancy, it is important to control disease activity and to achieve clinical remission for at least 6 months before pregnancy [20]. Adverse live-birth outcome was significantly correlated with low pre-gestational serum albumin level, elevated gestational anti-dsDNA antibody, and diabetes mellitus. Spontaneous abortion was directly correlated with low levels of pre-gestational serum albumin, positive anticardiolipin IgA, anti-B2-glycoprotein IgM, and anti-La antibodies. The risk of obstetric complications and maternal mortality is high in patients with active LN associated with preexisting hypertension [21].

17.4.6 Hypercoagulability in SLE Pregnancy itself is a hypercoagulable state with fetal demise, thrombosis, and preeclampsia being associated with factor V Leiden mutation, prothrombin gene mutation 20210A, and deficiencies of anti-thrombin III, protein C, and protein S

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[22]. Pregnancy complications in SLE are rather common with maternal hypertensive complications occurring in 10–20%, preterm births in 20%, fetal growth restriction occurring in about 28%, and an average drop in fetal growth weight to around 16%. The increased stillbirth rate in SLE is fourfold greater than the general population [23]. Hence, SLE-specific thrombophilic factors are additive to the background of pregnancy-­ related hypercoagulability (multiple hits). Collectively, this encourages the occurrence of worse fetal outcomes in lupus. Hypercoagulability in SLE is due to multiple factors (multiple-hit theory) (a) Lupus-specific procoagulant factors-APLA (antiphospholipid antibodies). (b) Other lupus-specific factors include antibodies to factor XII, prothrombin, and annexin V [24]. (c) Lupus nonspecific factors. (d) Non-lupus-related procoagulant factors. Chronic inflammation happening in SLE patients contributes to the occurrence of thrombosis. The factors responsible for this state can be summarized into: 1. Elevated or activated procoagulant factors— factors 2, 7, 8, 9, and 10, VWF, and fibrinogen. 2. Reduced anticoagulant factors—protein C, S, antithrombin III. 3. Inhibition of fibrinolysis  – PAI-1 elevation, hyperhomocysteinemia. 4. Elevated ESR, CRP, high-sensitivity CRP (HsCRP), complement activation, fibrinogen. 5. Increase in proinflammatory cytokines: IL-1, IL-6, tumor necrosis factor (TNF), and vascular endothelial growth factor (VEGF) [24].

17.4.6.1 Platelet Activation The prothrombotic effects of antiphospholipid antibodies occur through different mechanisms. They include platelet activation, endothelial cell activation with resultant upregulation of adhesion molecules and production of thromboxane A2, and stimulation of monocytes to make tissue factor.

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Ultimately, all this will enhance clotting and vasoconstriction. Tissue factor activates the extrinsic coagulation system, while tissue plasminogen activator (tPA) activates fibrinolysis. Tissue factor pathway inhibitor activity is diminished in SLE, and this is correlated with elevated levels of tissue factor and subsequent hypercoagulability [25].

17.4.6.2 Lupus Platelets Inflammatory process in SLE leads to release of tissue factor which further leads to platelet activation. The antiphospholipid antibodies bind to activated platelet membrane ultimately leading to hyperfunction of platelets similar to sticky platelet syndrome. Hyperfunction of platelets in SLE is one of the important factors in causation of thrombosis [26]. 17.4.6.3 Laboratory Workup In general, more than basic tests are needed to evaluate the full range of possibly disrupted clotting mechanisms. This involves testing for lupus-­specific antiphospholipid antibodies and other hemostatic markers of coagulation. The lupus-­specific antibodies include lupus anticoagulant, anticardiolipin antibodies, and anti-β-2 glycoprotein-­ 1 antibodies. These antiphospholipid antibodies are a heterogeneous group of antibodies identified by various laboratory techniques; each of them has some problems with standardization, specificity, interpretation, and quality control [27]. The target antigens for these different antibodies involve prothrombin and negatively charged phospholipids [28]. Apart from antiphospholipid antibodies, a coagulation risk laboratory profile also necessitates to be checked in lupus patients with thrombosis and fetal loss. Such profile includes testing for fibrinogen, factor VII, factor VIII, tPA, PAI-1, plasminogen activity, von Willebrand factor activity and antigen, protein C activity, protein S activity, homocysteine, and high-sensitivity C-reactive protein (Hs-CRP) [29]. 17.4.6.4 High-Risk Clinical Scenarios Selecting SLE patients for a coagulation assessment is well recognized for those with a thrombosis or fetal loss but is not well outlined for those who are at risk but have not yet had an

H. Al-Osaimi and A. Althubiti Table 17.2  High-risk lupus pregnancy High-risk lupus pregnancy Renal involvement High-dose steroid therapy Cardiac involvement Pre-estrogen therapy Pulmonary Pre-tamoxifen therapy hypertension Interstitial lung disease Pre-organ transplantation Active lupus disease Chronic inflammation Multiple pregnancy Immobility Immunosuppressive therapy Pre-vascular (cyclophosphamide, procedures (stent placements, etc.) methotrexate, etc.) Extractable nuclear Multiple antiphospholipid antigens (Ro, La) antibodies

event. Therefore, patients who have had an event should obviously be selected for a coagulation workup. The high-risk scenarios which needed workup are given in Table 17.2.

17.4.6.5 Management of Lupus Pregnancy Ideally, management of lupus pregnancy should begin before the onset of pregnancy. Thus, at preconception counseling, the physician not only estimates the risk profile of the patients but also reviews their drugs. The aim is to avoid known teratogenic drugs, to discontinue certain medications, and to initiate other drugs. This had been the golden goal to protect the mother and fetus from adverse effects of these medications. Hence, it is important to monitor the mother for at least 6 months before attempting conception. This is to assure a better outcome in lupus pregnancy. There is a need for different subspecialists like rheumatologist, obstetrician, nephrologist, and neonatologist, to come together in managing such high-risk lupus pregnancy with close monitoring. A) Management Issues Once results are positive for pregnancy, we should have a baseline assessment of the disease activity, severity of the disease, and major organ involvement. • Prenatal care visits: Every 4  weeks up to 20 weeks, then every 2 weeks until 28 weeks, and then weekly until delivery [Table 17.3].

17  Gestational Rheumatology Table 17.3  Guidelines in the assessment of pregnant patients with lupus First trimester

Second trimester

Third trimester

Each visit

• Baseline CBC, electrolytes, serum creatinine, liver enzymes, uric acid. • Fasting blood glucose, fasting lipid profile if at high risk, for example, if patient is nephritic or on steroids. • Normal antenatal checkup. • ANA, anti-dsDNA, anti-Ro and anti-La, antibody titers. • Complements levels (C3,C4,CH50). • Anticardiolipin antibodies, lupus anticoagulant, and β2 glycoprotein. • Urinalysis, 24-hour urine collection for measurement of protein and creatinine clearance. • Baseline laboratory studies. • Anti-dsDNA. • Complement levels (C3, C4, CH50), urinalysis. • Obstetric ultrasound: Every 4 weeks from 20 weeks of gestation until delivery “to monitor fetal growth”. • Mother with positive anti-Ro and/or anti-La antibodies, serial fetal echocardiography between 16 and 18 weeks of gestation. • Repeated laboratory studies. • Urinalysis, 24-hour urine protein collection if proteinuria is present. • Weekly fetal non-stress test (NST) and/or biophysical profile (BPP) scoring from 28 weeks gestation. • Fetal Doppler ultrasonography to be done in presence of intrauterine growth restriction. • Careful blood pressure measurement. • Urine dipstick for proteinuria.

Owing to the advancement of treatment interventions, more and more women with SLE are able to become pregnant. Pregnancy outcomes have improved noticeably over the last 40 years, with a decrease in pregnancy loss rate from a mean of 43% in 1960–1965 to 17% in 2000– 2003 [30]. Pregnant patients with SLE on immunosuppressive therapy should receive prophylaxis for infection (including antibiotics for invasive pro-

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cedures) and immunization with influenza and pneumococcal vaccine. Other goals to achieve in managing a lupus pregnancy are: 1 . Checking for high-risk clinical settings. 2. Performing coagulation risk lab profile in high-risk cases. 3. Assessment of the number and degree of procoagulant hits. 4. Prevention of thrombosis and adverse fetal outcomes. 5. Treatment of active lupus disease. 6. Treatment of hypercoagulable state. 7. Ensuring safety of medications used in treatment of the disease. Treatment of hypercoagulable state: 1. Thromboprophylaxis for acute high-risk conditions. 2. Chronic prophylaxis for thrombosis prevention. 3. Full treatment dose anticoagulation therapy for thrombosis. Thromboprophylaxis is controversial for patients with positive antiphospholipid antibodies (aPLs) but without any clinical history of thrombosis. However, evaluating risk of thrombosis by evaluating the multiple hits with a full thrombophilia profile would provide good support for deciding on intensity and type of thromboprophylactic treatment. For example, in pregnant SLE patients who are positive for lupus anticoagulant, it is recommended to use low-dose molecular weight or unfractionated heparin during pregnancy because neither can cross the placenta [31]. Treatment for acute arterial or venous thrombosis consists of an initial course of unfractionated or low molecular weight heparin followed by long-term treatment with warfarin to keep the international normalized ratio (INR) between 2.0 and 3.0. Heparin-type drugs or, more recently,

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one of the newer thrombin or factor Xa inhibitors can be used. For arterial thrombosis (stroke, myocardial infarction), addition of antiplatelet agents (low-dose aspirin, clopidogrel 75  mg) may be helpful, particularly if platelet hyperfunction is present [32]. Treatment for antiphospholipid syndrome (APS) is detailed in the section of antiphospholipid syndrome. B) Treatment of Active Lupus Activity SLE is common in women in the childbearing age. Physicians should be competent in the safe use of medications at preconception, conception, and during lactation. They should also be competent in addressing the effects of certain drugs on infants. The Food and Drug Administration (FDA) has a classification system for pregnancy risk. The pharmacological management of SLE could be puzzling as it has an unpredictable clinical course, with different organ system involvement and the absence of clear understanding of disease pathogenesis [33]. As hypertensive disorders of pregnancy are the leading cause of maternal mortality and morbidity, the target blood pressure of less than 140/90 is to be achieved. The safer antihypertensive drugs in pregnancy based on the evidence relate to parenteral hydralazine or labetalol and oral labetalol, nifedipine, or methyldopa [34]. Treatment with low doses of aspirin during pregnancy would be indicated in women with SLE, APS, hypertension, history of preeclampsia, and renal disease. Low dose of aspirin is safe throughout pregnancy. Women who took aspirin had a significantly lower risk of preterm delivery than those treated with placebo, but there is no significant difference in perinatal mortality [35]. NSAID should be used in the lowest effective dose and should be withdrawn before 8 weeks of expected date of delivery [36]. Nevertheless, because of the shared character of inhibition of prostaglandin synthesis, adverse effects like constriction of the ductus arteriosus in utero, renal dysfunction in the neonate, persistent pulmonary hypertension, increased maternal blood loss, and prolongation of pregnancy and labor are all possible when administered to pregnant patients.

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Hydroxychloroquine (HCQ) is now considered an extremely essential therapeutic choice in the treatment of lupus. These drugs are highly effective for discoid lupus erythematosus (DLE) cutaneous lesions. HCQ improves photosensitive skin lesions and prevents lupus flares [37]. Studies have confirmed that HCQ can preclude renal and central nervous system lupus. It also exerts the role of a prophylactic agent against some of the major comorbidities of SLE and its treatment, namely, hyperlipidemia, diabetes mellitus, and thrombosis [38]. More recently, chloroquine and HCQ have been shown to improve survival in a cohort of 232 SLE patients after adjusting for patient characteristics and disease activity [39]. It has been recently suggested that HCQ may affect TLR9 (toll-like receptor 9) activation and IFN-alpha production. From all of these perspectives, this drug is now considered an extremely essential therapeutic choice in the management of lupus. Steroids are used in pregnant SLE, and safety is not a major concern for their use in pregnancy based on the clinical indication. But one needs to look into the maternal morbidity it causes like maternal hypertension, gestational diabetes, infection, weight gain, acne, and proximal muscle weakness. Consequently, close monitoring is essential with the use of the lowest possible dose of corticosteroid needed to control disease flare along with vitamin D and calcium supplement [40]. There are few immunomodulator drugs that are used in SLE patients such as cyclophosphamide, methotrexate, mycophenolate mofetil, cyclosporine, azathioprine, and rituximab. The use of these drugs needs a thorough discussion with the pregnant lupus patient before starting them. As most of these drugs are classified by FDA as pregnancy risk category B and few as category X or D, they need to be shifted to azathioprine which is found to be safe in pregnancy [41]. Plasmapheresis and intravenous immunoglobulin (IVIG), the other two modalities of treatments used in lupus patients, are safe in pregnancy, but they are costly with very few indications.

17  Gestational Rheumatology

C) Delivery SLE is not an indication for delivery by cesarean section, and one should allow for vaginal delivery as much as possible [42]. There should be a team approach to the pregnant women with SLE. This is to guarantee a safe vaginal delivery and allow performing a cesarean section for obstetric indications only. The indications for cesarean section are the same as in other conditions. D) Puerperium The optimum management does not stop with the birth of a healthy baby. Actually, postpartum period should be addressed as high risk for pregnant lupus patients with several possible complications. The mother can suffer a lupus flare. Several studies have confirmed the postpartum period is specifically high risk for increased lupus activity. A close surveillance in the first 4  weeks after delivery is thus warranted, especially in patients with recent activity or with a previous history of severe disease. However, no specific prophylactic therapy, such as increasing the dose of steroid, is recommended. Thromboembolic risk is also high during the puerperium [43]. SLE is a chronic multisystem disease occurring in young women in their childbearing age. Therefore, the collaboration of rheumatologists and obstetricians who are experienced in high-­ risk pregnancies management is essential for managing pregnant patients with SLE. The aim is to have successful outcomes for both the disease and the pregnancy. Some manifestations of normal pregnancy can be misinterpreted as signs of lupus activity. Thus, understanding of pregnancy and lupus interaction has resulted in better approaches of monitoring and treating this particular clinical condition.

17.5 Antiphospholipid Syndrome in Pregnancy 17.5.1 Introduction APS or Hughes’ syndrome is a multisystem autoimmune disorder with hypercoagulable state

391

characterized by thrombosis (arterial, venous, or small blood vessels) or some obstetric complications (recurrent spontaneous abortions, stillbirth, preterm delivery, or severe preeclampsia) in the presence of antiphospholipid antibodies [44]. In 50% of the cases, it is primary (PAPS), and in the rest, it is secondary (SAPS) to any autoimmune disease particularly SLE. APS is the most common cause of acquired thrombophilia and is a known risk factor for the development of deep vein thrombosis (DVT) with or without pulmonary embolism, new strokes in individuals below the age of 50, and recurrent fetal loss [45]. APS is seen in 0.5% in the general population and 1–5% in healthy women of childbearing age. The antiphospholipid antibodies are present in 30–40% of SLE patients, and up to a third of these patients develop clinical manifestations of APS, especially venous or arterial thromboses. Majority of these patients (85–90% of the cases) are seen in the females in the reproductive age group [46].

17.5.2 Diagnostic Criteria The 1999 Sapporo criteria is replaced by revised Sydney criteria in 2006. Since then many research work was done, but the criteria remain the same as in 2006 [47]. The clinical criteria include any of the followings: 1. Vascular (arterial, venous, or small vessel) thrombosis excluding superficial thrombosis. 2. Pregnancy morbidity. (a) ≥1 unexplained deaths of a morphologically normal fetus at or beyond ≥10 gestational weeks (GW) (b) ≥1 premature births of a morphologically normal neonate ≤34 GW due to severe preeclampsia, eclampsia, or severe placental insufficiency (c) ≥3 unexplained consecutive spontaneous abortions ≤tenth GW (Excluding anatomic or hormonal defects or maternal/ paternal chromosomal causes).

392

The laboratory criteria include the presence of any one of the three antibodies on two occasions at least 12 weeks apart. They are lupus anticoagulant (LA), anticardiolipin antibodies (aCL-IgG or IgM), or anti-β2-glycoprotein 1 antibody (aβ2GP1-IgG or IgM). LA is to be tested 2–3 weeks after discontinuation of warfarin. One clinical criteria and one antibody test are required for diagnosis of APS. The aPL should be in medium or high titers at least tested twice >12  weeks apart. The strict objective criteria laid down for each clinical criterion should be fulfilled for the diagnosis of APS. aPLs are not only seen in APS (primary or secondary) but also in other diseases (syphilis, Lyme disease, CMV, EBV, HIV, HCV, and varicella) or patients on phenothiazines or even in normal general population. Therefore, the tests for aPL need to be repeated and established that these aPLs are persistently elevated and in medium or high titers to separate the APS patients from other causes of elevated aPL [47].

H. Al-Osaimi and A. Althubiti

VIIa, factor XI, factor XII, complement component C4, heparan sulfate proteoglycan, heparin, and oxidized low-density lipoproteins [49]. Negatively charged phospholipids exposed on the outer side of cell membranes attract the main autoantigens. This is happening excessively under special circumstances such as injury, apoptosis (e.g., endothelial cell), or after activation (e.g., platelets) [49]. The aPL acts on the clotting regulatory proteins like annexin A5, prothrombin, factor X, protein C, and plasmin, thereby promoting thrombosis [50]. Anti-β2GP1 disrupts the anticoagulant annexin A5 shield on trophoblast and endothelial cell monolayers causing a procoagulant state which subsequently leads to infarction and thrombosis of the placenta [49]. The activated platelets by aPL lead to increased expression of GPIIb/IIIa followed by synthesis of thromboxane A2 thereby causing a procoagulant state [51].

17.5.3.2 Defective Placentation Defective placentation is either due to impairment of invasion of trophoblast or inhibition of 17.5.3 Pathogenesis of APS endometrial angiogenesis. Anti-β2GP1 is the most important antibody responsible for this Thrombotic and non-thrombotic mechanisms mechanism. This antibody directly binds to the (inflammatory complement mediated) were pro- maternal decidua causing exposure of the cell posed to explain the clinical manifestations in membrane of the syncytiotrophoblast followed obstetric APS.  In the last decade, the non-­ by injury, apoptosis, inhibition of proliferation, thrombotic mechanism proved to be the most and formation of syncytia [52]. This results in important one causing cellular activation of defective secretion of growth factors and endothelial cells, neutrophils, monocytes, and decreased production of human chorionic gonadplatelets leading to upregulation of tissue factor otropin (HCG), thereby causing impaired inva(TF) ultimately activating the coagulation path- sion of trophoblast [52]. The aPL binds to human way [48]. endometrial epithelial cells (HEEC) on maternal Obstetric APS complications are explained by side inhibiting angiogenesis [53]. Endometrial three mechanisms: angiogenesis and decidualization are fundamental prerequisites for successful implantation and 17.5.3.1 Thrombosis (Thrombosis placental development. of Vessels and Placenta) The main target antigens described in patients 17.5.3.3 Inflammation with APS include anti-β2GP1/cardiolipin, pro- A physiological development of pregnancy thrombin, and annexin V which accounts for requires a fine regulation of the maternal immune more than 90% of antibody-binding activity. The response during implantation of embryo. Acute other targeted antigens are thrombin, protein C, inflammatory events are recognizable causes of protein S, thrombomodulin, tissue plasminogen adverse pregnancy outcomes through proinflamactivator, kininogens, prekallikrein, factor VII/ matory mediators, such as complement, tumor

17  Gestational Rheumatology

necrosis factor-alpha (TNF-alpha), and chemokines [54]. The aPLs induce an inflammatory response leading to compliment activation (both classical and alternate pathways with excessive generation of C3a and C5a), activation of endothelial cells and monocytes, upgrading of TF and release of inflammatory mediators like intracellular adhesion molecule (ICAM), vascular cell adhesion molecule (VCAM), selectins, TNF-alpha, and interleukins (ILs) resulting in poor pregnancy outcome [55]. A new probable mechanism of aPL-mediated fetal loss linking TF and complement activation has been recently explained. TF, best known as the primary cellular initiator of blood coagulation, also contributes to different biological processes. Although APS is a thrombophilic disorder, it needs a triggering factor popularly known as “second hit” (inflammation, tobacco, estrogens, etc.) to complete the cascade of thrombosis [56]. PAPS is a hereditary condition without a known cause and more often seen in patients with genetic marker HLA-DR7. SAPS is secondary to a known autoimmune disease, out of which the commonest is SLE.  Other diseases where it could also be seen are rheumatoid arthritis, scleroderma, Sjogren’s syndrome, Behcet’s disease, psoriatic arthritis, and temporal arteritis. It is also common in individuals with genetic markers: HLA-B8, HLA-DR2, and HLA-DR3, and it is also seen more in blacks, Hispanics, and Asians [57].

17.5.4 Treatment 17.5.4.1 L  ow-Dose ASA (LDA): Either Alone or Combined with Heparin Pregnant women with aPL positivity should be stratified in order to administer the optimal treatment. The recommended treatment of established APS in pregnancy generally consists of aspirin combined with heparin. LMWHs are at least as effective as unfractionated heparin and are safer [58]. The rationale of this combination is that aspirin may inhibit aPL-mediated hypercoagu-

393

lopathy in the intervillous space of the placenta. Heparin on the other hand may prevent aPLs from interfering with cytotrophoblast migration and promote blastocyst implantation in addition to prevention of venous thrombosis [59]. Prophylaxis and treatment of pregnancy with positive aPLs are shown in the flow chart (Fig. 17.1).

17.5.4.2 Aspirin/Heparin-Resistant APS (AHR-APS) At least 20% of the patients do not respond to the recommended treatment, and there is no approved treatment for this group of patients. Nevertheless, since recurrence of thrombotic events occurs despite the therapy and thrombosis cannot account for all of the histopathological findings in placenta from women with APS, other suggested mechanisms of reproductive impairment were expected to be involved [60] in obstetrical APS. The most essential mechanism for heparin to protect placenta in APS emerges to be its ability to prevent the binding of aPL antibodies to trophoblast cells. Recent studies showed that heparin also acts by inhibiting the endometrial angiogenesis and now several trials go on to demonstrate the beneficial effects of neutralizing antibodies by using synthetic peptides using β2GPI epitopes [61]. The AHR cases, which are approximately 20%, need to be approached differently. If they are resistant to conventional treatment of aspirin and heparin (unfractionated), it is better to give LMWH, particularly tinzaparin, which is found to be more effective or switch to fondaparinux with vitamin D supplements. If still not effective, the next step is to add high-dose HCQ (400– 800  mg/day) or low-dose prednisolone (10– 15 mg/day). Further resistance is counteracted by adding prednisolone to HCQ. If it is found still to be ineffective, then add pentoxifylline or IVIG in order for the treatment to be more effective. Apart from these drugs, there are others which are being tried in resistant cases of APS.  These include the combination of antiplatelet agents like aspirin and dipyridamole (adenosine uptake inhibitor), rituximab, homocysteine, direct thrombin inhibitors (dabigatran), oral direct fac-

394 Fig. 17.1  Flow Chart for Management of Aps Pregnant Patient (R. Handa, 2006) (aCL=anti-cardiolipin antibody; LA=lupus anticoagulant; αβ2GP1=anti-β2 – Glycoprotein 1 antibody; HCQ=Hydroxy Choloroquin; anti-TNF drugs = Anti-Tumor Necrotic Factor drugs; IVIG=Intravenous Immunoglobulin)

H. Al-Osaimi and A. Althubiti Pregnant lupus patient

LA, aCL (IgG or IgM) or aβ2GPI (IgG or IgM)

No History of Pregnancy loss

History of Pregnancy loss

Low antibody titers

High antibody titers

ASA + LMWH

No Treatment Needed

ASA 81 mg OD

REFRACTORY CASES HCQ, Prednisolone, Pentoxifylline, anti-TNF drugs, IVIG

tor Xa inhibitors (rivaroxaban or apixaban), dilacept (an adenosine uptake inhibitor, similar to dipyridamole) [62], defibrotide (a single-stranded DNA derivate), and histone deacetylase inhibitors which act to inhibit endothelial or monocyte TF expression [63].

Recently inflammatory theory is gaining more importance, and accordingly management by drugs other than aspirin with heparin seems to play a prominent role in the future. However, this requires well-designed double-blind placebo-­ controlled randomized trials.

17.5.5 Conclusion

17.6 Neonatal Lupus Erythematosus

APS is a preventable and treatable thrombophilic multisystem autoimmune disorder causing two clinically important manifestations, namely, thrombosis and obstetric complications like recurrent consecutive spontaneous abortions, stillbirths, premature deliveries, and pregnancy-­ induced hypertension. It is a commonly prevalent disorder which needs high index of suspicion to diagnose early and offer prophylactic and therapeutic management. The cornerstone of management is low-dose aspirin with or without heparin based on the popular theory of thrombosis.

17.6.1 Introduction Neonatal lupus erythematosus (NLE) or neonatal lupus syndrome is a rare syndrome seen in 1–2% of neonates with autoantibodies to SSA/Ro, SSB/ La, and/or U1 RNP passively transferred transplacentally from the mother. Such a mother is either asymptomatic or having manifestations of SS, SLE, or other systemic rheumatic disease. NLE is distinguished by cutaneous, cardiac, or rarely both clinical manifestations.

17  Gestational Rheumatology

17.6.2 Pathogenesis and Clinical Features

395

or second-degree heart block found in infants at birth can progress to CHB [67]. It may take just 1 week for a neonate to develop CHB from a norThe skin manifestation is appreciated at least in mal PR interval. Therefore, weekly fetal echocar30% of these patients. This may present in the diography is essential between 16 and 24 weeks. form of periorbital annular erythematous plaques The diagnosis of NLE is made when a fetus or later spreading to other areas of the face, scalp, newborn of a mother with anti-SSA/Ro and/or trunk, and extremities. It is non-scarring and non-­ anti-SSB/La or anti-RNP antibodies develops atrophic and usually transient lasting for days to heart block and/or the typical rash or hepatic or months. The cardiac manifestation is seen in up hematologic manifestations in the absence of to 60% of the patients. It is mainly in the form of other causes. complete congenital heart block (CHB). This is Women who test positive for SSA/Ro and irreversible and associated with cardiomyopathy SSB/La autoantibodies may benefit from more in at least 10% of the cases. CHB is also associ- intense evaluation for fetal heart block. This ated with higher morbidity and mortality. Almost requires frequent fetal echocardiographic testing all the patients with cardiac lupus require perma- weekly from the 16th through the 26th week of nent pacemaker. The recurrence rate of NLE is as pregnancy and then every other week until much as 25% in the following pregnancies. There 32  weeks. The most vulnerable period for the has been better understanding of etiopathogene- fetus is during the period from 18 to 24  weeks sis of the disease in the recent past due to rapid gestation. Normal sinus rhythm can progress to development in field of medicine [64]. complete block in 7  days during this high-risk NLE is presumed to result from transplacental period. New onset heart block is less likely from passage of maternal anti-SSA/Ro and/or anti-­ 26 to 30  weeks, and it rarely develops after SSB/La autoantibodies. These autoantibodies 30 weeks of pregnancy. Fetoscope auscultation to enter the myocardial cell resulting in exaggerated detect heart blocks by detecting bradycardia, bioapoptosis. This leads to expression of these anti- physical profile scoring, and non-stress testing bodies on the surface of the cardiocyte. It is pos- can also be used to diagnose CHB [68]. tulated that resident cardiocyte participates in physiologic clearance of apoptotic cells. However, clearance is now inhibited by opso- 17.6.3 Treatment of Congenital Heart Block nization through these maternal autoantibodies. This results in accumulation of these apoptotic cells promoting inflammation and stimulating The ultimate treatment for CHB is prevention as macrophages. Consequently, these macrophages once it is diagnosed, medical treatment seems to secrete cytokines mainly transforming growth be less favorable. Testing for culprit antibodies is factor-beta (TGF-β) that stimulate fibroblast pro- essential prior to initiating therapy for a preliferation. Ultimately, this leads to fibrosis of the sumed case of neonatal cardiac lupus (NCL) as conduction system (causing CHB) or myocar- there are cases of heart block not associated with dium (leading to cardiomyopathy or endocardial anti-SSA/Ro and SSB/La antibodies. The incifibroelastosis) or both [65, 66]. dence of CHB is only 2% in the offspring of Presentation in the neonate could be in the unselected anti-Ro antibody positive mothers. form of bradycardia, intermittent cannon waves Therefore, the preventative therapy cannot be in the neck, varying intensity of first heart sound, recommended for this group. Yet, in women with intermittent gallops, and murmurs. The newborn a previous child with CHB, the risk is greater, in is at greatest risk with a rapid atrial rate, often the range of 17–19%. Graham Hughes has sug150 beats/min or faster, and a ventricular rate less gested that in this group of patients, maternal than 50 beats/min with junctional or atrioventric- administration of intravenous immunoglobulins ular (AV) nodal escape or ectopic rhythm. First- (IVIG) may cut the risk of recurrences. Another

396

possible strategy to avoid recurrence in subsequent pregnancies is immune suppression with fluorinated steroids, which cross the placenta. However, the toxicity of these agents prevents their use as a preventative therapy [69]. A case-­ control study proposed that using HCQ, a ­toll-­like receptor (TLR) inhibitor may decrease the risk of NCL related to anti-SSA/SSB antibodies [67]. Treatment of different degrees of heart blocks is variable. Complete heart block is permanent, and nothing could reverse it even with glucocorticoid therapy [70]. On the other hand, second-­ degree heart block may be reversible. Unfortunately, it may progress to complete heart block despite therapy [71]. The clinical consequence of first-degree heart block is uncertain, since development from first-degree block to more advanced heart block in untreated fetuses has not been reported. Fluorinated glucocorticoids such as dexamethasone and betamethasone, which are not inactivated by placental 11-beta hydroxysteroid dehydrogenase, may suppress the associated pleuropericardial effusion or hydrops and may improve outcomes. Fluorinated glucocorticoids are also considered for signs of a more global cardiomyopathy. Maternal dexamethasone in conjunction with transplacental β-adrenergic stimulation for bradycardia in fetus with HR of 30 months

–– Increased fluid in the tendon sheath of the long head of the biceps. –– Increased vascularity around the intra-­ articular portion of the biceps tendon and the coracohumeral ligament. • MRI shows a thickening of the joint capsule and the coracohumeral ligament. It is useful in some conditions like rotator cuff tendinopathy and concomitant glenohumeral osteoarthritis for accurate diagnosis.

21.7.4 Treatment In most cases, frozen shoulder is a self-limited condition, although a complete resolution does not occur in many patients. • Physical therapy. • Nonsteroidal anti-inflammatory drugs (NSAIDs) and analgesics. • Intra-articular steroid injections. • Surgery in severe non-responding cases.

21.8 Neuropathic Osteoarthropathy (Charcot Joint) Neuropathic osteoarthropathy, also known as Charcot osteoarthropathy, is a progressive destructive process affecting the bone and joint structures associated with various diseases in

454

A. Monjed

which neuropathy occurs. However, DM is by far the most common aetiology.

21.8.1 Pathogenesis

decreased sensation due to a sensory neuropathy, which results in increased damage with microfractures (Fig. 21.3).

21.8.2 Epidemiology

The pathogenesis remains uncertain, but it is probably due to an underlying diabetic peripheral neuropathy and a combination of mechanical trauma and vascular factors. It may result from repeated trauma, often minor, in the setting of

• Among the general diabetic population, neuroarthropathy is uncommon, affecting approximately 1  in 700 diabetic patients [30, 31].

Diabetes Mellitus

Motor Neuropathy

Sensory Neuropathy

Decrease muscles strength

Loss of proprioception

Instability

Repetitive minor trauma

DIABETIC NEUROPATHIC ARTHROPATHY

Ulceration and infection

Fig. 21.3  Pathogenesis of diabetic neuropathic arthropathy

Autonomic Neuropathy

Decrease perfusion to skin, bone, and surrounding joint

21  Diabetes and Rheumatology

455

Table. 21.4  The Modified Eichenholtz System to Stage Charcot Joint Progression Inflammatory (Stage 0)

Development (Stage 1)

 Localized swelling, erythema, and warmth



Persistent swelling, redness, and warmth

 No radiological abnormalities



Bony changes such as fracture, subluxation, dislocation



Bony debris starts to appear radiologically

• Patients at risk are usually those who have longstanding diabetes (average duration 15 years) with peripheral neuropathy and are in their sixth or seventh decade [30, 31].

21.8.3 Approach to Charcot Joint 21.8.3.1 History • Arthritis and swollen foot or ankle (although may occur in any joint). • The modified Eichenholtz system was developed to stage the progression of Charcot joint and to recommend treatment based on the clinical stage and radiographic changes [32] (Table. 21.4). 21.8.3.2 Physical Examination • Serial X-rays with different findings according to the stage. –– Inflammatory stage: no radiological abnormalities. –– Development stage: joint effusion, subluxation, bone destruction and osteochondral fragmentation. –– Coalescence stage: periosteal new bone formation, subchondral sclerosis, resorption of debris, marginal osteophytes. –– Remodelling stage: ankylosis or rounded bone ends, decreased sclerosis, decreased swelling. • MRI: may show bone marrow oedema, bone bruising or microfractures.

Coalescence (Stage 2) 

Inflammatory signs decrease



Radiological signs of fracture healing, bony debris resorption



New bone formation

Remodeling (Stage 3) 

Clinical inflammatory signs have settled



Bony deformity



Radiologically, may show mature fracture and decreased sclerosis

21.8.4 Treatment • Avoidance of weight bearing is the mainstay of treatment. It should be for at least 3 months or until erythema and oedema resolve accompanied by radiographic improvements. • NSAIDs. • Calcitonin and bisphosphonates may be added on to limb offloading. Their use has not been approved yet in the treatment of Charcot neuroarthropathy [35, 36]. • Surgical treatment may only be required when the conservative treatment fails or severe deformities developed. (Table 21.5) Summary of the Most Common Rheumatological Diseases/Complications in Diabetic Patients.

21.9 Diabetes and Osteoporosis Both diabetes and osteoporosis are prevalent diseases with significantly associated mortalities and morbidities. It has been well established that diabetic patients are at increased risk of osteoporosis and fractures, particularly at the hip. Osteoporosis is defined as a combination of reduced bone mass and altered bone quality, with microarchitectural abnormalities, resulting in decreased bone strength with an increased risk of fractures [37, 38]. At present, the diagnosis of osteoporosis rests on bone mineral density

456

A. Monjed

(BMD) measurement using dual-energy X-ray absorptiometry (DXA). The results are reported as the difference, in standard deviations (SDs),

with the peak bone mass (−score). The World Health Organization (WHO) defines osteoporosis as a BMD -score of −2.5 or less [37–39].

Table 21.5  Summary of the Most Common Rheumatological Diseases/Complications in Diabetic Patients

Syndromes of limited joint mobility

Pathophysiology

Symptoms

Investigations

Treatment

- Painless stiffness of small joints in the - Glucose level hand - Imaging: - Decreased grip U/S strength MRI - Prayer sign test - Table top test

- Improve glycemic control - NSAID - Corticosteroid injection - Physiotherapy - Surgery

Dupuytren’s contracture

Same as other limited joint, leading to fibroblastic proliferation and collagen deposition

- Finger stiffness, usually the 3rd & 4th digits in DM - Thickening or a palpable nodule in the palm - Loss of motion of the affected fingers

Clinical diagnosis

Mild disease: - physiotherapy Moderate: - corticosteroid injection Contracture: - surgery

Trigger finger (Stenosing flexor tenosynovitis)

Inflammation of flexor tendons in hand leading to thickening

- Finger pain - Locking of finger in flexed position

- Active movement - Clinical diagnosis - Splinting - X- ray - NSAIDs - Biopsy - Steroid injection

Diabetic cheiroarthropathy (Stiff-hand syndrome) (8-50% among diabetics)

Binding of advanced glycosylation end products to collagen that is deposited around joints

Adhesive capsulitis Same as other limited - Shoulder stiffness - Painful shoulder joint mobility (Frozen shoulder) - Loss of motion

Neuropathy

Rheumatological complication of diabetes

Rheumatological diseases

- Physiotherapy - Clinical diagnosis - NSAID - U/S, MRI, and - Steroid injection plain X-rays - Surgery

Neuropathic arthritis (Charcot joints)

Mechanical and vascular factors resulting from diabetic peripheral neuropathy

- Arthritis - Swollen foot - Foot arch collapse

- Clinical diagnosis - X- ray - MRI -

Weight-bearing limitation NSAIDs Surgery

Carpal tunnel syndrome (CTS)

Neuropathy of diabetes causes nerve compression

- Numbness - Pain - Weakness

- Phalen test - Tinnel test - Nerve conduction study+/-EMG

-

Splinting NSAIDs Steroid injection Surgery

Diabetic Amyotrophy

Ischemic injury from a non-systemic micro vasculitis

- Acute local pain, followed by weakness in the proximal leg - Autonomic failure and weight loss

- CBC, FBS, HbA1C ESR - EMG, nerve conduction study - MRI and CT

Tricyclic antidepressant Steroids Immunotherapy

Reflex sympathetic dystrophy

Neuropathic complication of DM with autonomic symptoms

1st stage: burning throbbing pain & edema 2nd stage: ↑ edema & - Autonomic tests - X-ray, CT, MRI skin thickening - Bone 3rd stage: limitation scintigraphy of movement and contracture, waxy trophic skin changes, and brittle nails

- Education - Physical therapy - Analgesics, corticosteroids, oral muscle relaxants, bisphosphonates, and calcium-channel blockers - Invasive: intravenous percutaneous sympathetic blockade, surgical sympathectomy, spinal cord stimulation, and amputation

(continued)

21  Diabetes and Rheumatology

457

Table 21.5 (continued)

Diffuse idiopathic skeletal hyperostosis (DISH) (Non-inflammatory disease with calcification and ossification of spinal ligament and entheses)

Rheumatological complication of diabetes

Rheumatologic al diseases

Pathophysiology

• Etiology: unknown, could be due to abnormal osteoblastic activity at the enthesis. • Insulin-like growth factor-1, insulin, glucose, and growth hormone are involved in the pathogenesis of osteoblastic activity in DISH. • Other factors : prolonged exposure to Vitamin A and fluoride. usage of Isotretinoin. Mechanical: Dextrocardia

Symptoms

Investigations

• Radiologically: • Neck, thoracic • Plain X-ray: spine, low back, Thoracic: or extremities longitudinal pain calcification • Disability and and spinal morning ossification stiffness Cervical: • May be associated Hyperostosis with dysphagia, with stridor, apnea, downward hoarseness, or pointing spurs Lumbar: thoracic outlet Hyperostosis syndrome due to with upward large anterior pointing spurs cervical • CT: is more osteophytes sensitive in • O/E: ↓ range of detecting spinal motion posterior with tender calcifications entheses

Treatment

Symptomatic relief: • Physical therapy • Analgesia: NSAIDs or local steroid • Surgery: If dysphagia, myopathy, or thoracic outlet syndrome developed

Criteria for diagnosis of DISH: • Resnick and Niwayama Criteria:[31] 1. Presence of longitudinal ossification and calcification on the anterior surface of at least, 4 consecutive vertebral bodies. 2. Absence of degenerative radiological changes in discs involved with preservation of intervertebral space. 3. Absence of apophyseal joint bony ankylosis and sacroiliac joint erosion or sclerosis.

Diabetic Muscular Infarction

• Utsinger Criteria:[32] 1. Ossification, fine and ribbon-like wave, along the anterolateral aspect of at least 4 consecutive vertebrae. 2. Ossification on the anterolateral aspect of at least 2 consecutive vertebral bodies. 3. Presence of peripheral and symmetrical entheses pathology, involving heel, patella and olecranon, with new bone formation. 1 = definite, 2 or 3 = probably.

• Painful and swollen leg: commonly involving thigh +/- calf muscles Hyperglycemia has many adverse effects on arterial • Mild fever without infectious vasculature as well as signs or platelets and coagulation factors leading to symptoms occlusion of the vessels • History of trauma • Compartment syndrome (less common)

• • • •

CK elevation U/S MRI Muscle biopsy to confirm the diagnosis

• Analgesia • Anti-platelets (ASA) • NSAIDs • Surgical excision of infarcted tissues

ASA, asprin, CBC, complete blood count; CK, creatinine kinase; CT, computed tomography; EMG, electromyography; ESR, erythrocyte sedimentation rate; FBG, fasting blood glucose; MRI, magnetic resonance imaging; NSAIDs, non-steroidal anti-inflammatory drugs; O/E, on examination; U/S, ultrasound

458

21.9.1 Pathogenesis Type I diabetes is associated with bone fragility and loss of bone mass, while type II diabetes, despite having a normal or an increased bone mineral density (BMD), is associated with bone quality deterioration that cannot be diagnosed by using dual-energy X-ray absorptiometry (DXA).

Box 21.1 Risk Factors for Fractures in Diabetic Patients [37, 40]

1. Type of diabetes I or II, poor glycaemic control, and risk of drug-induced hypoglycaemia. 2. Microvascular complications of diabetes, especially nephropathy and neuropathy. 3. Type I diabetes-associated diseases such as autoimmune hyperthyroidism, amenorrhea, eating disorders and celiac disease. 4. Increased risk of falls due to diabetes-­ related complications such as hypoglycaemia, poor vision and/or balance, autonomic orthostatic hypotension and arthropathy. 5. Vitamin D deficiency, which is more common in diabetics than general population.

21.9.2 Challenges in Diagnosing and Treating Diabetes-Related Osteoporosis Although the risk has been well established, it remains underappreciated in the major international diabetes guidelines and by most clinicians caring for diabetic patients. There have been also insufficient studies evaluating the effectiveness and long-term safety of the available therapeutic antiporotic modalities to reduce the risk of fracture in patients with diabetes.

A. Monjed

21.9.3 Approach to Diabetes-Related Osteoporosis 21.9.3.1 History • Type of diabetes and glycaemic control (frequency of hyper- and hypoglycaemia). • Symptoms of diabetes-related microvascular complications. • Assess any risk for falls. • Ask about any of the following risk factors that might increase the risk of osteoporotic fractures: –– Previous history of fracture. –– Parental history of hip fracture. –– Smoking. –– Alcoholism. –– Steroid use. –– Hyperthyroidism, celiac disease, hyperparathyroidism, vitamin D deficiency or rheumatoid arthritis. 21.9.3.2 Physical Exam • Height measurement for any loss of height. • Body mass index (low BMI